JP2013519724A - Pyrazolopiperidine derivatives as NADPH oxidase inhibitors - Google Patents

Abstract

The present invention relates to pyrazolopiperidine derivatives of formula (I), pharmaceutical compositions thereof, and these for treating and / or preventing disorders or medical conditions associated with reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) About the use of.

Description

  The present invention relates to pyrazolopiperidine derivatives of formula (I), pharmaceutical compositions thereof, and cardiovascular diseases, respiratory disorders, disorders affecting metabolism, skin and / or bone diseases, neurodegenerative diseases, renal diseases, It relates to their use for preparing medicaments for treating and / or preventing reproductive disorders, inflammatory disorders and cancer. Specifically, the present invention relates to a pyrazolopiperidine derivative useful for the preparation of a pharmaceutical preparation that modulates, particularly inhibits, the activity or function of reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase).

NADPH oxidase (NOX) is a protein that transports electrons through biological membranes. Generally, the electron acceptor is oxygen and the product of the electron transfer reaction is superoxide. Thus, the biological function of the NOX enzyme is to generate reactive oxygen species (ROS) from oxygen. Reactive oxygen species (ROS) are small molecules derived from oxygen, such as oxygen radicals (superoxide anion [ ^● O ₂ ⁻ ], hydroxyl [HO ^● ], peroxyl [ROO ^● ], alkoxyl [RO ^● ], and hydro peroxyl [HOO ^●]), as well as whether the oxidizing agent, and / or are easily converted into radicals, including certain non-radicals. Nitrogen containing oxidizing agents (eg, nitric oxide) are also referred to as active nitrogen species (RNS). The production of ROS is generally a series of reactions beginning with the production of superoxide. Superoxide spontaneously disproportionates rapidly to hydrogen peroxide, especially at low pH or by superoxide dismutase catalyst. Other elements of the series of ROS generation include reaction of superoxide and nitric oxide to generate peroxynitrite, generation of hypochlorous acid from hydrogen peroxide by peroxidase catalyst, and iron catalyst to generate hydroxyl radical A Fenton reaction is mentioned.

  ROS interacts strongly with many other small molecules, including small molecules including DNA, proteins, lipids, carbohydrates and nucleic acids. This initial reaction generates a second radical, which can increase the possible damage. ROS is involved not only in cell damage and pathogen death, but also in many reversible regulatory processes in almost all cells and tissues. However, although ROS is important in controlling basic physiological processes, the generation of ROS may irreversibly destroy or alter the function of the target molecule. As a result, ROS is increasingly understood as a major factor for biological organism damage (so-called “oxidative stress”).

  During inflammation, NADPH oxidase is one of the most important sources of ROS in vascular cells in the inflammatory state (Thabut et al., 2002, J. Biol. Chem., 277: 22814-22821).

  In the lung, tissue is generated oxidant endogenously by metabolic reactions (eg, mitochondrial respiration, or activation of incorporated inflammatory cells) or exogenously in the atmosphere (eg, tobacco smoke or air pollution). Is always exposed to. In addition, the lungs are constantly exposed to high oxygen pressure compared to other tissues, have a much larger surface area and blood supply, and are particularly susceptible to ROS-mediated damage (Brigham, 1986, Chest, 89 (6): 859-863). There has been a description of NADPH oxidase-dependent ROS generation in lung endothelial cells and smooth muscle cells. Activation of NADPH oxidase in response to stimulation has been implicated in the progression of respiratory disorders (eg, pulmonary hypertension) and increased pulmonary vasoconstriction (Djordjevic et al., 2005, Artioscler. Thromb). Vas.Biol., 25, 519-525; Liua et al., 2004, Am. J. Physiol. Lung, Cell. Mol. Physiol., 287: L111-118). Furthermore, pulmonary fibrosis has been characterized by pulmonary inflammation and excessive ROS generation.

  Osteoclasts are macrophage-like cells that play an important role in bone turnover (eg, bone resorption) and produce ROS by a mechanism dependent on NADPH oxidase (Yang et al., 2002, J. Cell. Chem. 84, 645-654).

  Diabetes is known to increase oxidative stress in both humans and animals (eg, increased ROS production due to sugar auto-oxidation), and increased oxidative stress plays an important role in the development of diabetic complications It has been said. Increased localization of peroxide and endothelial dysfunction in the central retina of diabetic rats has been shown to occur in the same space as the region with NADPH oxidase activity in retinal endothelial cells (Ellis et al., 2000, Free Rad. Biol. Med., 28: 91-101). Furthermore, it has been suggested that controlling oxidative stress (ROS) in mitochondria and / or inflammation may be a valuable approach to treating diabetes (Pillarisetti et al., 2004, Expert Opin. Ther. Targets, 8 (5): 401-408).

  ROS is also generally strongly associated with the pathogenesis of cardiovascular diseases such as atherosclerosis, cell proliferation, hypertension and reperfusion injury (Cai et al., 2003, Trends Pharmacol. Sci., 24: 471-478). All risk factors for atherosclerosis, for example, not only increase superoxide production in the arterial wall, but ROS also elicits many “promoting atherogenesis” cellular responses in vitro. An important result when ROS is produced in vascular cells is the consumption of carbon monoxide (NO). NO suppresses the progression of vascular disease, and the absence of NO is important for the pathogenesis of cardiovascular disease. It has been reported that NADPH oxidase activity is increased in the vessel wall after balloon injury (Shi et al., 2001, Throm. Vasc. Biol., 2001, 21, 739-745).

  Oxidative stress or free radical damage is also believed to be a major cause of neurodegenerative diseases. Such injuries include mitochondrial abnormalities, neuronal demyelination, apoptosis, neuronal death, reduced cognitive ability, and may develop progressive neurodegenerative disorders (Nunomura et al., 2001, J Neuropathol Exp. Neurol., 60: 759-767; Giroard, 2006, J. Appl.Physiol. 100: 328-335).

  Furthermore, the production of ROS in semen has been shown in many species and has been suggested to be due to NADPH oxidase in sperm (Vernet et al., Biol. Reprod., 2001, 65: 1102-1113). . Excessive ROS production has been implicated in semen lesions, such as male infertility, and certain penile disorders and prostate cancer.

  NADPH oxidase is an enzyme having a plurality of subunits composed of a cytochrome b558 domain that binds to a membrane and three cytoplasmic protein subunits: p47phox, p67phox, and Rac, which is a low molecular weight GTPase. Seven isoforms of the NOX enzyme have been identified, including NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 (Leto et al., 2006, Antioxidid Redox Signal, 8 (9-10): 1549-61; Cheng et al., 2001, Gene, 16; 269 (1-2): 131-40).

  Thus, ROS derived from NADPH can cause many diseases, particularly cardiovascular diseases or disorders, respiratory disorders or diseases, diseases or disorders affecting metabolism, bone disorders, neurodegenerative diseases, inflammatory diseases, reproductive disorders or Causes disease, pain, cancer, and gastrointestinal diseases or disorders. Therefore, it would be highly desirable to develop new active agents that focus on the ROS signaling cascade, particularly NADPH oxidase (NOX).

  The present invention relates to disorders associated with reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), such as cardiovascular diseases, respiratory disorders, disorders affecting metabolism, skin and / or bone diseases, neurodegeneration. Disease, kidney disease, reproductive disorder, inflammatory disorder, cancer, allergic disorder, traumatic symptoms, septic shock, hemorrhagic shock and anaphylactic shock, gastrointestinal disease or disorder, angiogenesis, angiogenesis dependent pathology It relates to novel molecules useful for the treatment and / or prevention. In particular, the present invention relates to novel molecules useful for suppressing or reducing ROS production in cells.

The first aspect of the present invention is a pyrazolopiperidine derivative of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined below), and their tautomers, geometric isomers, optically active Forms, pharmaceutically acceptable salts and pharmaceutically active derivatives are provided. However, this compound is not selected from the group consisting of:
5-methyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-ethyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-phenyl-5-propyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-butyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (3-methylbutyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-Benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one.

A second aspect of the present invention provides a pyrazolopiperidine derivative of formula (I) for use as a medicament, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined below), and tautomers, geometric isomers thereof. Body, optically active forms, pharmaceutically acceptable salts and pharmaceutically active derivatives.

  A third aspect of the present invention provides a pyrazolopiperidine derivative of the present invention and at least one of its pharmaceutically acceptable salt and pharmaceutically active derivative and its pharmaceutically acceptable carrier, diluent or The present invention relates to a pharmaceutical composition containing an excipient.

  The fourth aspect of the invention affects cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammation and / or neurodegenerative disorders, kidney disease, reproductive disorders, eyes and / or lenses Conditions affecting the disease and / or inner ear, inflammatory disorders, liver disease, pain, cancer, allergic disorders, traumatic symptoms, septic shock, hemorrhagic shock and anaphylactic shock, gastrointestinal diseases or disorders, angiogenesis Preparation of a pharmaceutical composition for treating or preventing a disease or condition selected from a pathology and / or other diseases dependent on angiogenesis and a disorder related to reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) For preparing a pyrazolopiperidine derivative of the present invention, and a pharmaceutically acceptable salt thereof. Fine pharmaceutically in the use of active derivatives.

The fifth aspect of the invention affects cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammation and / or neurodegenerative disorders, renal diseases, reproductive disorders, eyes and / or lenses Conditions affecting the disease and / or inner ear, inflammatory disorders, liver disease, pain, cancer, allergic disorders, traumatic symptoms, septic shock, hemorrhagic shock and anaphylactic shock, gastrointestinal diseases or disorders, angiogenesis And a method of treating a patient suffering from a disease or condition selected from angiogenesis-dependent medical conditions and other diseases and / or disorders associated with reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase). This method involves the preparation of a pyrazolopiperidine derivative of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined below), and tautomers, geometric isomers, optically active forms, pharmaceutically Administering acceptable salts and pharmaceutically active derivatives to a patient in need thereof.

The sixth aspect of the invention affects cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammation and / or neurodegenerative disorders, renal diseases, reproductive disorders, eyes and / or lenses Conditions affecting the disease and / or inner ear, inflammatory disorders, liver diseases, pain, cancer, allergic disorders, traumatic symptoms, septic shock, hemorrhagic shock and anaphylactic shock, gastrointestinal diseases or disorders, angiogenesis For treating a disease or condition selected from angiogenesis-dependent medical conditions and other diseases and / or disorders associated with reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) the pyrazolo piperidine derivative ^{(wherein, R 1, R 2, R} 3, R 4, R 5, R 6, R 7, R 8, R ^{, R 10, R 11, R} 12, R 13, R 14, R 15, R 16 and ^{R 17} are as defined below.) As well as tautomers thereof, geometric isomers, optically active Form, pharmaceutically acceptable salts and pharmaceutically active derivatives.

  Other features and advantages of the present invention will become apparent from the following detailed description.

  The following paragraphs provide definitions of the various chemical moieties that make up the compounds of the present invention, and these definitions should be used in the description and claims, unless the definitions specified otherwise give a broader definition. It shall be applied uniformly over the entire range.

The term “alkyl”, when used alone or in combination with other terms, refers to a straight or branched C ₁ -C ₂₀ alkyl, which refers to a monovalent alkyl group containing from 1 to 20 carbon atoms. including. Examples of this term include, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- Methylhexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, tetrahydrogeranyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-octadecyl, n-nonadecyl, a group such as n-eicosanyl; Preferably, these comprise C ₁ -C ₉ alkyl, more preferably C ₁ -C ₆ alkyl, particularly preferably C ₁ -C ₄ alkyl, in other words, 1 to 9 carbon atoms, respectively. A monovalent alkyl group containing 1, a monovalent alkyl group containing 1 to 6 carbon atoms, and a carbon atom containing 1 to 4 carbon atoms. In particular, these include C ₁ -C ₆ alkyl.

The term “alkenyl”, when used alone or in combination with other terms, includes straight or branched C ₂ -C ₂₀ alkenyl. There may be any available number of double bonds at any available position, and the arrangement of double bonds may be (E) or (Z). Examples of this term are, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -Heptenyl, 1-octenyl, geranyl, 1-decenyl, 1-tetradecenyl, 1-octadecenyl, 9-octadecenyl, 1-eicocenyl, 3,7,11,15-tetramethyl-1-hexadecenyl and the like. Preferably, it _is C 2 -C ₈ alkenyl, more preferably _C 2 -C ₆ alkenyl. Of these, vinyl or ethenyl (—CH═CH ₂ ), n-2-propenyl (allyl, —CH ₂ CH═CH ₂ ), isopropenyl, 1-propenyl, 2-methyl-1-propenyl, -Butenyl, 2-butenyl, 3-methyl-2-butenyl and the like.

The term “alkynyl” when used alone or in combination with other terms includes straight or branched C ₂ -C ₂₀ alkynyl. There may be any available number of triple bonds at any available position. Examples of this term are, for example, alkynyl groups which may have 2 to 20 carbon atoms and optionally have a double bond, for example ethynyl (—C≡CH), 1-propynyl, 2-propynyl. (Propargyl: —CH ₂ C≡CH), 2-butynyl, 2-penten-4-ynyl and the like. In particular, these include C ₂ -C ₈ alkynyl, more preferably C ₂ -C ₆ alkynyl and the like. Preferably, these include C ₂ -C ₆ alkynyl, which refers to groups containing 2 to 6 carbon atoms and containing at least one or two alkynyl unsaturations.

The term “heteroalkyl” refers to C ₁ -C ₁₂ -alkyl, preferably C ₁ -C ₆ -alkyl, wherein at least one carbon is replaced with a heteroatom selected from O, N or S; 2-methoxyethyl and the like are included.

  The term “aryl” refers to an unsaturated aromatic carbocyclic group containing 6 to 14 carbon atoms containing a single ring (eg, phenyl) or an unsaturated aromatic containing 6 to 14 carbon atoms containing multiple condensed rings. Refers to a carbocyclic group (eg, indenyl, naphthyl). Aryl includes phenyl, naphthyl, anthryl, phenanthrenyl and the like.

The term “C ₁ -C ₆ alkylaryl” refers to an aryl group containing a C ₁ -C ₆ alkyl substituent, including methylphenyl, ethylphenyl, and the like.

The term “aryl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing an aryl substituent, including 3-phenylpropanyl, benzyl, and the like.

  The term “heteroaryl” refers to a monocyclic heteroaromatic or bicyclic or tricyclic fused-ring heteroaromatic group. Specific examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1 , 2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, , 2,3-triazinyl, benzofuryl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1,2 -A] pyridyl, benzothiazolyl Benzoxazolyl, quinolidinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido [3,4-b] pyridyl, pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, quinolyl, isoquinolyl, Examples include tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthreninyl, or benzoquinolyl.

The term “C ₁ -C ₆ alkylheteroaryl” refers to a heteroaryl group containing a C ₁ -C ₆ alkyl substituent, including methylfuryl and the like.

The term “heteroaryl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing a heteroaryl substituent, including furylmethyl and the like.

The term “C ₂ -C ₆ alkenyl aryl” refers to an aryl group that includes a C ₂ -C ₆ alkenyl substituent, including vinyl phenyl and the like.

The term “aryl C ₂ -C ₆ alkenyl” refers to a C ₂ -C ₆ alkenyl group containing an aryl substituent, including phenyl vinyl and the like.

The term “C ₂ -C ₆ alkenyl heteroaryl” refers to a heteroaryl group containing a C ₂ -C ₆ alkenyl substituent, including vinyl pyridinyl and the like.

The term “heteroaryl C ₂ -C ₆ alkenyl” refers to a C ₁ -C ₆ alkenyl group containing a heteroaryl substituent, including pyridinyl vinyl and the like.

The term “C ₃ -C ₈ -cycloalkyl” refers to a saturated carbocyclic group having 3 to 8 carbon atoms containing a single ring (eg, cyclohexyl), or 3 to 8 carbon atoms containing multiple condensed rings. Refers to a saturated carbocyclic group (eg, norbornyl). C ₃ -C ₈ -cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl and the like.

The term “heterocycloalkyl” refers to a C ₃ -C ₈ -cycloalkyl group in accordance with the above definition, wherein up to 3 carbon atoms are replaced with a heteroatom selected from the group consisting of O, S, NR. And R refers to a group defined as hydrogen or methyl. Heterocycloalkyl includes pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and the like.

The term “C ₁ -C ₆ alkyl C ₃ -C ₈ -cycloalkyl” refers to a C ₃ -C ₈ -cycloalkyl group containing a C ₁ -C ₆ alkyl substituent, including methylcyclopentyl and the like.

The term “C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing a C ₃ -C ₈ -cycloalkyl substituent, including 3-cyclopentylpropyl and the like.

The term “C ₁ -C ₆ alkylheterocycloalkyl” refers to a heterocycloalkyl group containing a C ₁ -C ₆ alkyl substituent, including 4-methylpiperidinyl and the like.

The term “heterocycloalkyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing a heterocycloalkyl substituent, including (1-methylpiperidin-4-yl) methyl and the like.

  The term “carboxy” refers to a —C (O) OH group.

The term “carboxy C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing a carboxy substituent, including 2-carboxyethyl and the like.

The term “acyl” refers to a —C (O) R group, where R is H, “C ₁ -C ₆ alkyl”, preferably “C ₁ -C ₆ alkyl”, “aryl”, “hetero “Aryl”, “C ₃ -C ₈ -cycloalkyl”, “heterocycloalkyl”, “aryl C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl”, “C ₃ -C ₈ -cycloalkyl” C ₁ -C ₆ alkyl ”or“ heterocycloalkyl C ₁ -C ₆ alkyl ”), acetyl and the like.

The term “acyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing an acyl substituent, including 2-acetylethyl and the like.

  The term “acylaryl” refers to aryl groups that contain an acyl substituent, including 2-acetylphenyl and the like.

The term “acyloxy” refers to the group —OC (O) R, where R is H, “C ₁ -C ₆ alkyl”, “C ₂ -C ₆ alkenyl”, “C ₂ -C ₆ alkynyl”. , “C ₃ -C ₈ -cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, “aryl C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl”, “aryl” “C ₂ -C ₆ alkenyl”, “heteroaryl C ₂ -C ₆ alkenyl”, “aryl C ₂ -C ₆ alkynyl”, “heteroaryl C ₂ -C ₆ alkynyl”, “C ₃ -C ₈ -cycloalkyl C” ₁ -C ₆ alkyl "or" heterocycloalkyl _C 1 -C ₆ alkyl "and the like), and the like acetyloxy.

The term “acyloxy C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing an acyloxy substituent, including 2- (ethylcarbonyloxy) ethyl and the like.

The term “alkoxy” refers to the group —O—R, where R is “C ₁ -C ₆ alkyl”, “aryl”, “heteroaryl”, “aryl C ₁ -C ₆ alkyl”, or “ include heteroaryl _C 1 -C ₆ alkyl ". Preferable alkoxy groups include methoxy, ethoxy, phenoxy and the like.

The term “alkoxy C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing an alkoxy substituent, including methoxyethyl and the like.

The term “alkoxycarbonyl” refers to a —C (O) OR group, where R is “C ₁ -C ₆ alkyl”, “aryl”, “heteroaryl”, “aryl C ₁ -C ₆ alkyl”. , “Heteroaryl C ₁ -C ₆ alkyl”, or “heteroalkyl”.

The term “alkoxycarbonyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing an alkoxycarbonyl substituent, including 2- (benzyloxycarbonyl) ethyl and the like.

The term “aminocarbonyl” refers to the group —C (O) NRR ′ where R and R ′ are each independently H, C ₁ -C ₆ alkyl, aryl, heteroaryl, “aryl C ₁ -C ₆ alkyl ", or" heteroaryl _C 1 -C ₆ alkyl "), and the like N- phenylcarbonyl.

The term “aminocarbonyl C ₁ -C ₆ alkyl” refers to an alkyl group containing an aminocarbonyl substituent, including 2- (dimethylaminocarbonyl) ethyl, N-ethylacetamidyl, N, N-diethyl-acetamidyl, and the like. .

The term “acylamino” refers to the group —NRC (O) R ′, wherein R and R ′ are each independently H, “C ₁ -C ₆ alkyl”, “C ₂ -C ₆ alkenyl”. , “C ₂ -C ₆ alkynyl”, “C ₃ -C ₈ -cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, “aryl C ₁ -C ₆ alkyl”, “heteroaryl C” ₁ -C ₆ alkyl "," aryl _C 2 -C ₆ alkenyl "," heteroaryl _C 2 -C ₆ alkenyl "," aryl _C 2 -C ₆ alkynyl "," heteroaryl _C 2 -C ₆ alkynyl "," cycloalkyl _C 1 -C ₆ alkyl ", or" heterocycloalkyl _C 1 -C ₆ alkyl "), and the like acetylamino.

The term “acylamino C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing an acylamino substituent, including 2- (propionylamino) ethyl and the like.

The term “ureido” refers to the group —NRC (O) NR′R ″, where R, R ′ and R ″ are each independently H, “C ₁ -C ₆ alkyl”, “C ₂ -C ₆ alkenyl "," alkynyl "," _C 3 -C ₈ - cycloalkyl "," heterocycloalkyl "," _C 1 -C ₆ aryl "," heteroaryl "," aryl _C 1 -C ₆ alkyl " , “Heteroaryl C ₁ -C ₆ alkyl”, “aryl C ₂ -C ₆ alkenyl”, “heteroaryl C ₂ -C ₆ alkenyl”, “aryl C ₂ -C ₆ alkynyl”, “heteroaryl C ₂ -C ₆ alkynyl ”,“ cycloalkyl C ₁ -C ₆ alkyl ”, or“ heterocycloalkyl C ₁ -C ₆ alkyl ”and R ′ and R ″ together with the nitrogen atom to which they are attached In combination, a 3- to 8-membered heterocycloalkyl ring may be formed.

The term “ureido C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing a ureido substituent, including 2- (N′-methylureido) ethyl and the like.

The term “carbamate” refers to the group —NRC (O) OR ′, where R and R ′ are each independently “C ₁ -C ₆ alkyl”, “C ₂ -C ₆ alkenyl”, “ “C ₂ -C ₆ alkynyl”, “C ₃ -C ₈ -cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, “C ₁ -C ₆ alkylaryl”, “heteroaryl C _1- ” “C ₆ alkyl”, “aryl C ₂ -C ₆ alkenyl”, “heteroaryl C ₂ -C ₆ alkenyl”, “aryl C ₂ -C ₆ alkynyl”, “heteroaryl C ₂ -C ₆ alkynyl”, “cycloalkyl” “C ₁ -C ₆ alkyl” or “heterocycloalkyl C ₁ -C ₆ alkyl”, optionally R may be hydrogen.

The term “amino” refers to the group —NRR ′, wherein R and R ′ are each independently H, “C ₁ -C ₆ alkyl”, “aryl”, “heteroaryl”, “C ₁ -C ₆ alkyl aryl "," C ₁ -C ₆ alkyl heteroaryl ", a" cycloalkyl ", or" heterocycloalkyl ", and, R 'and R", together with the nitrogen atom to which they are attached In some cases, a 3- to 8-membered heterocycloalkyl ring may be formed.

  The term “aminoalkyl” refers to an alkyl group containing an amino substituent, including 2- (1-pyrrolidinyl) ethyl and the like.

The term “ammonium” refers to a positively charged —N ⁺ RR′R ″ group, where R, R ′ and R ″ are each independently “C ₁ -C ₆ alkyl”, “C ₁ -C ₆ alkyl aryl "," C ₁ -C ₆ alkyl heteroaryl ", a" cycloalkyl ", or" heterocycloalkyl ", and, R 'and R", together with the nitrogen atom to which they are attached In some cases, a 3- to 8-membered heterocycloalkyl ring may be formed.

  The term “ammonium alkyl” refers to an alkyl group containing an ammonium substituent, including 1-ethylpyrrolidinium and the like.

  The term “halogen” refers to fluorine, chlorine, bromine and iodine atoms.

The term "sulfonyloxy" refers to _-OSO 2 -R group wherein R is _"C 1 -C ₆ alkyl" substituted with halogens _"C 1 -C ₆ alkyl", for example, -OSO ₂ - CF ₃ group, “C ₂ -C ₆ alkenyl”, “alkynyl”, “C ₃ -C ₈ -cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, “aryl C ₁ -C ₆ “Alkyl”, “heteroaryl C ₁ -C ₆ alkyl”, “aryl C ₂ -C ₆ alkenyl”, “heteroaryl C ₂ -C ₆ alkenyl”, “aryl C ₂ -C ₆ alkynyl”, “heteroaryl C ₂ Selected from “C ₆ alkynyl”, “cycloalkyl C ₁ -C ₆ alkyl”, or “heterocycloalkylalkyl”.

The term “sulfonyloxy C ₁ -C ₆ alkyl” refers to an alkyl group that contains a sulfonyloxy substituent, including 2- (methylsulfonyloxy) ethyl and the like.

The term "sulfonyl", - refers to _"SO 2 -R" group, wherein R is "aryl", "heteroaryl", _"C 1 -C ₆ alkyl" substituted with halogens _"C 1 -C _alkyl ", for _example, -SO 2 -CF ₃ group," _C 2 -C ₆ alkenyl "," _C 2 -C ₆ alkynyl "," _C 3 -C ₈ - cycloalkyl "," heterocycloalkyl "," “Aryl”, “heteroaryl”, “aryl C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl”, “aryl C ₂ -C ₆ alkenyl”, “heteroaryl C ₂ -C ₆ alkenyl”, "aryl _C 2 -C ₆ alkynyl", "heteroaryl _C 2 -C ₆ alkynyl", "cycloalkyl _C 1 -C ₆ alkyl" or "heterocycloalkyl _C 1 -C ₆ alkyl It is selected from.

The term “sulfonyl C ₁ -C ₆ alkyl” refers to an alkyl group containing a sulfonyl substituent, including 2- (methylsulfonyl) ethyl and the like.

The term “sulfinyl” refers to a “—S (O) —R” group, where R is “alkyl”, “alkyl” substituted with halogen, eg, —SO—CF ₃ group, “C _2- “C ₆ alkenyl”, “C ₂ -C ₆ alkynyl”, “C ₃ -C ₈ -cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, “aryl C ₁ -C ₆ alkyl”, “Heteroaryl C ₁ -C ₆ alkyl”, “aryl C ₂ -C ₆ alkenyl”, “heteroaryl C ₂ -C ₆ alkenyl”, “aryl C ₂ -C ₆ alkynyl”, “heteroaryl C ₂ -C ₆ It is selected from “alkynyl”, “C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl”, or “heterocycloalkyl C ₁ -C ₆ alkyl”.

  The term “sulfinylalkyl” refers to an alkyl group that contains a sulfinyl substituent, including 2- (methylsulfinyl) ethyl and the like.

The term "sulfanyl" refers to -S-R groups, wherein the R is H, _"C 1 -C ₆ alkyl" substituted with halogens _"C 1 -C ₆ alkyl", for example, -S- CF ₃ group, “C ₂ -C ₆ alkenyl”, “C ₂ -C ₆ alkynyl”, “C ₃ -C ₈ -cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, “aryl” “C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl”, “aryl C ₂ -C ₆ alkenyl”, “heteroaryl C ₂ -C ₆ alkenyl”, “aryl C ₂ -C ₆ alkynyl”, Examples include “alkynylheteroaryl”, “cycloalkyl C ₁ -C ₆ alkyl”, or “heterocycloalkyl C ₁ -C ₆ alkyl”. Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl and the like.

The term “sulfanyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₅ -alkyl group containing a sulfanyl substituent, including 2- (ethylsulfanyl) ethyl and the like.

The term “sulfonylamino” refers to the group —NRSO ₂ —R ′, wherein R and R ′ are each independently “C ₁ -C ₆ alkyl”, “C ₂ -C ₆ alkenyl”, “ “C ₂ -C ₆ alkynyl”, “C ₃ -C ₈ -cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, “aryl C ₁ -C ₆ alkyl”, “heteroaryl C _1- ” “C ₆ alkyl”, “aryl C ₂ -C ₆ alkenyl”, “heteroaryl C ₂ -C ₆ alkenyl”, “aryl C ₂ -C ₆ alkynyl”, “heteroaryl C ₂ -C ₆ alkynyl”, “C ₃ -C ₈ - cycloalkyl _C 1 -C ₆ alkyl ", or" heterocycloalkyl _C 1 -C ₆ alkyl ".

The term “sulfonylamino C ₁ -C ₆ alkyl” refers to an alkyl group that contains a sulfonylamino substituent, including 2- (ethylsulfonylamino) ethyl and the like.

The term “aminosulfonyl” refers to a —SO ₂ —NRR ′ group, wherein R and R ′ are each independently H, “C ₁ -C ₆ alkyl”, “C ₂ -C ₆ alkenyl”. , “C ₂ -C ₆ alkynyl”, “C ₃ -C ₈ -cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, “aryl C ₁ -C ₆ alkyl”, “heteroaryl C” ₁ -C ₆ alkyl "," arylalkenyl "," heteroaryl _C 2 -C ₆ alkenyl "," aryl _C 2 -C ₆ alkynyl "," heteroaryl _C 2 -C ₆ alkynyl "," _C 3 -C ₈ -Cycloalkyl C ₁ -C ₆ alkyl ”, or“ heterocycloalkyl C ₁ -C ₆ alkyl ”, and R and R ′ together with the nitrogen atom to which they are attached, May form a 3- to 8-membered heterocycloalkyl ring. Examples of the aminosulfonyl group include cyclohexylaminosulfonyl, piperidinylsulfonyl and the like.

The term “aminosulfonyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group containing an aminosulfonyl substituent, including 2- (cyclohexylaminosulfonyl) ethyl and the like.

  It is to be understood that all of the above substituents may be optionally substituted unless otherwise limited by the definition of individual substituents.

Unless otherwise limited by the definition of individual substituents, the term “substituted” means “C ₁ -C ₆ alkyl”, “C ₂ -C ₆ alkenyl”, “C _2- “C ₆ alkynyl”, “C ₃ -C ₈ -cycloalkyl”, “heterocycloalkyl”, “C ₁ -C ₆ alkyl aryl”, “C ₁ -C ₆ alkyl heteroaryl”, “C ₁ -C ₆ alkyl” “Cycloalkyl”, “C ₁ -C ₆ alkylheterocycloalkyl”, “amino”, “aminosulfonyl”, “ammonium”, “alkoxy”, “acylamino”, “aminocarbonyl”, “aryl”, “heteroaryl” , “Sulfinyl”, “sulfonyl”, “sulfonamide”, “alkoxy”, “alkoxycarbonyl”, “carbamate”, “sulfanyl”, A group substituted with 1 to 5 substituents selected from the group consisting of “halogen”, trihalomethyl, cyano, hydroxy, mercapto, nitro and the like.

  The term “pharmaceutically acceptable salt or complex” refers to a salt or complex of the compound of formula (I) specified below. Examples of such salts include, but are not limited to, compounds of formula (I) and organic or inorganic bases (eg, alkali metals (sodium, potassium or lithium), alkaline earth metals (eg, calcium or Bases made by reaction with hydroxides, carbonates or bicarbonates of metal cations, such as those selected from the group consisting of magnesium), or with primary, secondary or tertiary organic alkylamines Addition salts are mentioned. Methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, morpholine, N-Me-D-glucamine, N, N'-bis (phenylmethyl) -1,2-ethanediamine, tromethamine, ethanolamine, diethanolamine, ethylenediamine Amine salts derived from N-methylmorpholine, procaine, piperidine, piperazine and the like are envisioned to be within the scope of the present invention.

  Also, acid addition salts made using inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and organic acids (eg, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, Also included are salts made from acid addition salts made with fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, polygalacturonic acid) .

  “Pharmaceutically active derivative” refers to any compound capable of directly or indirectly conferring the activity disclosed herein upon administration to a recipient. The term “indirectly” also encompasses prodrugs that can be converted to the active form of the drug by endogenous enzymes or metabolism. Prodrugs are derivatives of the compounds of the invention that have chemically or metabolically degradable groups and exhibit NADPH oxidase inhibitory activity and are also pharmaceutically active in vivo by solvolysis under physiological conditions. It is a compound that can be converted into a new compound. Furthermore, the present invention includes any tautomers of the compounds of the present invention.

  The term “cardiovascular disorder or disease” refers to atherosclerosis, particularly but not limited to hypertension, cardiovascular complications of type I or type II diabetes, intimal hyperplasia, coronary heart disease, Cerebral, coronary or arterial vasospasm, endothelial dysfunction, heart failure including congestive heart failure, peripheral arterial disease, restenosis, stented trauma, stroke, ischemic stroke, vascular complications (eg after organ transplant) , Myocardial infarction, high blood pressure, atherosclerotic plaque formation, platelet aggregation, angina, aneurysm, aortic dissection, ischemic heart disease, cardiac hypertrophy, pulmonary embolism, thrombotic events including deep vein thrombosis, organ transplantation, etc. Injury after ischemia due to restoration of blood flow or oxygen delivery, open heart surgery, angioplasty, hemorrhagic shock, angioplasty of ischemic organs including heart, brain, liver, kidney, retina and intestine Of, including diseases or disorders associated with endothelial dysfunction.

  The term “respiratory disorder or disease” includes bronchial asthma, bronchitis, allergic rhinitis, adult respiratory syndrome, cystic fibrosis, viral infection of the lung (influenza), pulmonary hypertension, idiopathic pulmonary fibrosis, and chronic obstruction Infectious lung disease (COPD).

  The term “allergic disorder” includes hay fever and asthma.

  The term “traumatic condition” includes multiple trauma.

  The term “disease or disorder affecting metabolism” includes obesity, metabolic syndrome, type II diabetes.

  The term “skin disease or disorder” includes psoriasis, eczema, dermatitis, wound healing, and scar formation.

  The term “bone disorder” includes osteoporosis, osteoporosis, osteosclerosis, periodontitis, hyperparathyroidism.

  The term “neurodegenerative disease or disorder” includes diseases or conditions characterized by central nervous system (CNS) degeneration or changes, particularly degeneration or changes at the neuronal level, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Includes amyotrophic lateral sclerosis, epilepsy, and muscular dystrophy. In addition, it includes neuroinflammation and demyelinating conditions or diseases such as leukoencephalopathy, and cerebral leukotrophy.

  The term “demyelination” refers to a condition or disease of the CNS that involves the degeneration of myelin surrounding axons. In the context of the present invention, the term demyelinating disease refers to a condition involving the process of removing the myelination of cells, eg, multiple sclerosis, progressive multifocal leukoencephalopathy (PML), myelopathy, autoreactive leukocytes within the CNS. Neuropathy conditions involving the disease, inborn errors of metabolism, neuropathy with abnormal myelination, drug-induced demyelination, radiation-induced demyelination, congenital demyelination, prion-induced demyelination It is intended to include a condition, encephalitis-induced demyelination, or spinal cord injury. Preferably the condition is multiple sclerosis.

  The term “kidney disease or disorder” includes diabetic nephropathy, renal failure, renal fibrosis, glomerulonephritis, nephrotoxicity of aminoglycosides and platinum compounds, and overactive bladder. In certain embodiments, the term of the present invention includes chronic kidney disease or disorder.

  The term “reproductive disorder or disease” includes erectile dysfunction, infertility disorder, prostatic hypertrophy, and benign prostatic hypertrophy.

  The term “disease or disorder affecting the eye and / or lens” includes cataract including diabetic cataract, recorneal opacity of the lens after cataract surgery, and diabetic and other forms of retinopathy.

  The term “condition affecting the inner ear” refers to senile deafness, tinnitus, Meniere's disease, other imbalances, ovarian sac stones, vestibular migraine, noise-induced hearing loss, and drug-induced hearing loss (toxic hearing loss). )including.

  The term `` inflammatory disorder or disease '' includes inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, rheumatoid arthritis, Arteriosclerosis, cerebral hemorrhage, cerebral infarction, heart failure, myocardial infarction, psoriasis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchitis, chronic bronchiolitis, osteoarthritis, gout, myelitis, ankylos Spondylitis, Reuters syndrome, psoriatic arthritis, spondyloarthritis, juvenile arthritis or juvenile ankylosing spondylitis, reactive arthritis, infectious arthritis or post-infection arthritis, gonococcal arthritis, syphilitic arthritis, Lyme disease, "pulse Arthritis induced by "tubular inflammation syndrome", polyarteritis nodosa, anaphylaxis vasculitis, Lugenec granulomatosis, rheumatic polymyalgia, arthritis Rheumatism, calcium crystal deposition arthritis, pseudogout, non-articular rheumatism, bursitis, tendon synovitis, inflammation of the epicondyle (tennis elbow), carpal tunnel syndrome, impairment due to repeated use (typing), arthritis Mixed form, neuropathic arthropathy, hemorrhagic arthritis, vascular purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis induced by certain diseases, blood pigmentation, sickle cells Diseases and other hemoglobin abnormalities, hyperlipoproteinemia, gamma globulin abnormalities, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behcet's disease, systemic autoimmune diseases, lupus erythematosus, multiple sclerosis and In formula (I) at a dosage sufficient to inhibit Crohn's disease, or a disease such as relapsing polychondritis, chronic inflammatory bowel disease (IBD), or NADPH oxidase The the compound is meant a disease that is associated necessary to administer to a mammal an effective dosage for treatment.

  The term “liver disease or disorder” includes liver fibrosis, alcoholic liver fibrosis, steatosis, and nonalcoholic steatohepatitis.

  The term “arthritis” refers to acute rheumatoid arthritis, rheumatoid arthritis, chlamydia arthritis, chronic absorptive arthritis, chyle arthritis, arthritis from bowel disease, filariatic arthritis, gonococcal arthritis, gouty arthritis, hemophilia arthritis , Hypertrophic arthritis, juvenile chronic arthritis, Lyme arthritis, neonatal equine arthritis, nodular arthritis, alkaptonuria arthritis, psoriatic arthritis or purulent arthritis, or a formula of dosage sufficient to inhibit NADPH oxidase It means a related disease in which it is necessary to administer a compound represented by (I) to a mammal in a therapeutically effective dosage.

  The term “pain” includes hyperalgesia associated with inflammatory pain.

  The term “cancer” refers to a carcinoma (eg, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, hemangiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial, periosteum, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, kidney cancer, prostate cancer, squamous cell carcinoma, basal cell cancer, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary cancer, papillary gland Cancer, cystadenocarcinoma, medullary cancer, bronchial cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriomas, seminoma, fetal carcinoma, nephroblastoma, cervical cancer, testicular tumor, lung cancer, small cell lung cancer , Lung adenocarcinoma, bladder cancer or epithelial cancer), or a dosage of formula (I) sufficient to inhibit NADPH oxidase should be administered to the mammal in a therapeutically effective dosage Meaning related diseases.

  The term “gastrointestinal disease or disorder” includes gastric mucosal disorder, management of ischemic bowel disease, enteritis / colitis, cancer chemotherapy, or neutropenia.

  The term “angiogenesis” includes sprouting angiogenesis, intussusception angiogenesis, angiogenesis, arteriogenesis, and lymphangiogenesis. Angiogenesis is the formation of new blood vessels from preexisting capillaries or postcapillary venules and occurs in pathological conditions such as cancer, arthritis and inflammation. Organs composed of various tissues or systematic tissues undergo angiogenesis in disease states that include tissues such as skin, muscle, gastrointestinal tract, connective tissue, joints, and bones that can invade when vascularized. May help. As used herein, the term “angiogenesis-dependent pathology” is intended to mean a condition that maintains the process of angiogenesis or angiogenesis or enhances a pathological condition. Angiogenesis results from the generation of new blood vessels that arise from hemangioblasts, which are endothelial cell precursors. Both processes result in the formation of new blood vessels and are included within the meaning of the term pathology dependent on angiogenesis. Similarly, the term “angiogenesis” as used herein refers to the de novo formation of blood vessels such as those resulting from angiogenesis and those resulting from branching and sprouting of existing blood vessels, capillaries, venules. Shall be included.

  The term “inhibition of angiogenesis” means effective in reducing the extent, amount or rate of neovascularization. Influencing the decrease in the extent, amount or rate of endothelial cell proliferation or migration in tissue is a specific example of inhibiting angiogenesis. Antiangiogenic activity targets the tumor growth process, and in the absence of neovascularization of the tumor tissue, the tumor tissue does not get the necessary nutrients, slows growth, stops further growth, and regresses And eventually necrotic and the tumor dies, making it particularly useful in the treatment of any cancer. In addition, angiogenesis-inhibiting activity also requires metastasis formation to cause angiogenesis of the primary tumor, so metastatic cancer cells must exit the primary tumor and become established at the secondary site. Is particularly useful in the treatment of any cancer because it is particularly effective at forming metastases because of the need for neovascularization to support

  As used herein, “treatment” and “treating” generally mean obtaining desirable pharmacological and physiological effects. The effect may be prophylactic in terms of preventing or partially preventing a disease, disease symptom or condition, and / or resulting from a disease, condition, symptom, or disease It may be therapeutic in terms of partial or complete cure of adverse effects. The term “treatment”, as used herein, encompasses any treatment of diseases in mammals, particularly humans, and (a) subjects who are likely to be affected by a disease but have not yet been diagnosed as having the disease. Preventing the disease from developing in the specimen; (b) suppressing the disease, ie stopping its progression; or reducing the disease, ie restoring the disease and / or its symptoms or conditions Including that.

  The term “subject” as used herein refers to a mammal. For example, mammals contemplated by the present invention include humans, primates, livestock (eg, cows, sheep, pigs, horses) and the like.

  The term “inhibitor” as used in connection with the present invention is defined as a molecule that completely or partially suppresses the activity of NADPH oxidase and / or suppresses or reduces the production of reactive oxygen species (ROS). .

〔式中、Ｒ^１は、Ｈ；場合により置換されていてもよいアルコキシカルボニル；場合により置換されていてもよいＣ_１〜Ｃ_６アルキル、例えば、場合により置換されていてもよいメチル（例えば、メチル）、場合により置換されていてもよいエチル（例えば、２−ヒドロキシエチル）；場合により置換されていてもよいＣ_２〜Ｃ_６アルケニル；場合により置換されていてもよいＣ_２〜Ｃ_６アルキニル；場合により置換されていてもよいアルコキシ；場合により置換されていてもよいアルコキシＣ_１〜Ｃ_６アルキル、例えば、場合により置換されていてもよいアルコキシエチル、例えば、場合により置換されていてもよいフェノキシエチル（例えば、フェノキシエチル、４−クロロフェノキシエチル）、場合により置換されていてもよいメトキシエチル（例えば、２−メトキシエチル）；場合により置換されていてもよいアミノアルキル；場合により置換されていてもよいアシル；場合により置換されていてもよいアリール、例えば、場合により置換されていてもよいフェニル（例えば、フェニル、３−メトキシフェニル、２−メトキシフェニル、３−メトキシフェニル、４−メトキシフェニル、１−メトキシフェニル、３−ベンジルオキシフェニル、１−クロロフェニル、２−クロロフェニル、３−クロロフェニル、４−クロロフェニル、２−フルオロフェニル、２−クロロ−４−フルオロフェニル、３−フルオロフェニル、３−ベンゾニトリル、４−ベンゾニトリル、３−フェニルアセトアミド）；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルアリール；場合により置換されていてもよいアリールＣ_１〜Ｃ_６アルキル、例えば、場合により置換されていてもよいアリールメチル、例えば、場合により置換されていてもよいフェニルメチル（例えば、ベンジル、４−クロロベンジル、２−メトキシベンジル、３−メトキシベンジル、４−メトキシベンジル）；場合により置換されていてもよいヘテロアリール、例えば、場合により置換されていてもよいベンゾジオキソイル（例えば、１，３ ベンゾジオキソール−５−イル）、場合により置換されていてもよいベンゾチアゾリル（例えば、２−メチル １，３−ベンゾチアゾール−６−イル）；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルヘテロアリール；場合により置換されていてもよいヘテロアリールＣ_１〜Ｃ_６アルキル、例えば、場合により置換されていてもよいヘテロアリールメチル、例えば、場合により置換されていてもよいイミダゾ［１，２，ａ］ピリジン−２−イルメチル（例えば、２−イミダゾ［１，２，ａ］ピリジン−２−イルメチル）；場合により置換されていてもよいＣ_２〜Ｃ_６アルケニルアリール；場合により置換されていてもよいアリールＣ_２〜Ｃ_６アルケニル；場合により置換されていてもよいＣ_２〜Ｃ_６アルケニルヘテロアリール；場合により置換されていてもよいヘテロアリールＣ_２〜Ｃ_６アルケニル；場合により置換されていてもよいＣ_３〜Ｃ_８−シクロアルキル；場合により置換されていてもよいヘテロシクロアルキル、例えば、場合により置換されていてもよいピペリジン（例えば、（例えば、１−メチルピペリジン−４−イル、２−ピペリジン−１−イルエチル）；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルＣ_３〜Ｃ_８−シクロアルキル；場合により置換されていてもよいＣ_３〜Ｃ_８−シクロアルキルＣ_１〜Ｃ_６アルキル；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルヘテロシクロアルキルおよび場合により置換されていてもよいヘテロシクロアルキルＣ_１〜Ｃ_６アルキル、例えば、場合により置換されていてもよいヘテロシクロアルキルエチル、例えばモルホリニルエチル（例えば、２−モルホリン−４−イルエチル）または場合により置換されていてもよいピペリジンエチル（例えば、２−ピペリニン−１−イルエチル）から選択されるものであり；Ｒ^２は、Ｈ；場合により置換されていてもよいＣ_１〜Ｃ_６アルキル；場合により置換されていてもよいＣ_２〜Ｃ_６アルケニル；場合により置換されていてもよいＣ_２〜Ｃ_６アルキニル；場合により置換されていてもよいアリール；場合により置換されていてもよいヘテロアリール、例えば、場合により置換されていてもよいピリジンアルキル、例えば場合により置換されていてもよいピリジンメチル（例えば、ピリジン−３−イル−メチル）；場合により置換されていてもよいＣ_３〜Ｃ_８−シクロアルキル；場合により置換されていてもよいヘテロシクロアルキル；場合により置換されていてもよいＣ_３〜Ｃ_８−シクロアルキルＣ_１〜Ｃ_６アルキル；場合により置換されていてもよいヘテロシクロアルキルＣ_１〜Ｃ_６アルキル；場合により置換されていてもよいアリールＣ_１〜Ｃ_６アルキル、例えば、場合により置換されていてもよいフェニルアルキル、例えば場合により置換されていてもよいフェニルメチル（例えば、ベンジル）および場合により置換されていてもよいヘテロアリールＣ_１〜Ｃ_６アルキル、例えば、場合により置換されていてもよいヘテロアリールメチル、例えば場合により置換されていてもよいピリジンメチル（例えば、ピリジン−３−イルメチル）から選択されるものであり；Ｒ^３は、−Ｓ（Ｏ）−Ｒ^４、−Ｓ（Ｏ）_２−Ｒ^４、場合により置換されていてもよいＣ_３〜Ｃ_８−シクロアルキル、場合により置換されていてもよいヘテロシクロアルキルおよび−ＣＲ^５Ｒ^６Ｒ^７から選択されるものであり；Ｒ^４は、Ｈ；場合により置換されていてもよいアミノ；場合により置換されていてもよいＣ_１〜Ｃ_６アルキル、例えば、場合により置換されていてもよいメチル（例えば、メチル）；場合により置換されていてもよいＣ_２〜Ｃ_６アルケニル；場合により置換されていてもよいＣ_２〜Ｃ_６アルキニル；場合により置換されていてもよいアルコキシ；場合により置換されていてもよいアルコキシＣ_１〜Ｃ_６アルキル、例えば、場合により置換されていてもよいアミノアルキル；場合により置換されていてもよいアシル；場合により置換されていてもよいアリール、例えば、場合により置換されていてもよいフェニル（例えば、４−メチルフェニル）；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルアリール；場合により置換されていてもよいアリールＣ_１〜Ｃ_６アルキル、例えば、場合により置換されていてもよいアリールメチル；場合により置換されていてもよいヘテロアリール；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルヘテロアリール；場合により置換されていてもよいヘテロアリールＣ_１〜Ｃ_６アルキル；場合により置換されていてもよいＣ_２〜Ｃ_６アルケニルアリール；場合により置換されていてもよいアリールＣ_２〜Ｃ_６アルケニル；場合により置換されていてもよいＣ_２〜Ｃ_６アルケニルヘテロアリール；場合により置換されていてもよいヘテロアリールＣ_２〜Ｃ_６アルケニル；場合により置換されていてもよいＣ_３〜Ｃ_８−シクロアルキル；場合により置換されていてもよいヘテロシクロアルキル；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルＣ_３〜Ｃ_８−シクロアルキル；場合により置換されていてもよいＣ_３〜Ｃ_８−シクロアルキルＣ_１〜Ｃ_６アルキル；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルヘテロシクロアルキルおよび場合により置換されていてもよいヘテロシクロアルキルＣ_１〜Ｃ_６アルキルから選択されるものであり；Ｒ^５は、Ｈおよび−ＣＲ^８Ｒ^９Ｒ^１０から選択されるものであり；Ｒ^６は、Ｈおよび−ＣＲ^１１Ｒ^１２Ｒ^１３から選択されるものであり；Ｒ^７は、Ｈ、−ＣＲ^１４Ｒ^１５Ｒ^１６および−Ｃ（Ｏ）−Ｒ^１７から選択されるものであり；Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５、Ｒ^１６およびＲ^１７は、各々独立して、Ｈ；ハロゲン；場合により置換されていてもよいアミノ；場合により置換されていてもよいアシル；場合により置換されていてもよいＣ_１〜Ｃ_６アルキル、例えば、場合により置換されていてもよいアルコキシアルキル、例えばアルコキシメチル（例えば、２−フェノキシメチル）；場合により置換されていてもよいＣ_２〜Ｃ_６アルケニル；場合により置換されていてもよいＣ_２〜Ｃ_６アルキニル；場合により置換されていてもよいアリール；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルアリール；場合により置換されていてもよいアリールＣ_１〜Ｃ_６アルキル；場合により置換されていてもよいヘテロアリール；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルヘテロアリール；場合により置換されていてもよいヘテロアリールＣ_１〜Ｃ_６アルキル；場合により置換されていてもよいＣ_２〜Ｃ_６アルケニルアリール；場合により置換されていてもよいアリールＣ_２〜Ｃ_６アルケニル；場合により置換されていてもよいＣ_２〜Ｃ_６アルケニルヘテロアリール；場合により置換されていてもよいヘテロアリールＣ_２〜Ｃ_６アルケニル；場合により置換されていてもよいＣ_３〜Ｃ_８−シクロアルキル；場合により置換されていてもよいヘテロシクロアルキル；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルＣ_３〜Ｃ_８−シクロアルキル；場合により置換されていてもよいＣ_３〜Ｃ_８−シクロアルキルＣ_１〜Ｃ_６アルキル；場合により置換されていてもよいＣ_１〜Ｃ_６アルキルヘテロシクロアルキルおよび場合により置換されていてもよいヘテロシクロアルキルＣ_１〜Ｃ_６アルキルから選択されるものであり；−ＣＲ^８Ｒ^９Ｒ^１０、−ＣＲ^１１Ｒ^１２Ｒ^１３または−ＣＲ^１４Ｒ^１５Ｒ^１６は、各々独立して、場合により置換されていてもよいアリール、例えば、場合により置換されていてもよいフェニル（例えば、フェニル、３−シアノフェニル、４−シアノフェニル、２−クロロフェニル、３−クロロフェニル、４−クロロフェニル、１−クロロフェニル、２−クロロフェニル、４−ジクロロフェニル、３，４−ジクロロフェニル、３，５−ジクロロフェニル、３−トリフルオロメチルフェニル、４−メトキシフェニル、３−メトキシフェニル、４−メトキシフェニル、３−クロロ−４−フルオロフェニル
、３−フルオロ−４−シアノフェニル４−ベンジルオキシフェニル、４−メチルスルホニルフェニル、４−メチルフェニルアセトアミド、Ｎ−メチルフェニルアミド）；場合により置換されていてもよいヘテロアリール、例えば、場合により置換されていてもよいピリジン（例えば、ピリジン−２−イル、ピリジン−３−イル、６−クロロピリジン−３−イル）；場合により置換されていてもよいＣ_３〜Ｃ_８−シクロアルキル、または場合により置換されていてもよいヘテロシクロアルキルから選択される、場合により置換されていてもよい環を形成してもよい。〕、並びにその互変異性体、幾何異性体、光学的に活性な形態、医薬的に許容される塩、および医薬的に活性な誘導体を提供するが、ただし、この化合物は、下記からなる群から選択されるものではない。
５−メチル−２−フェニル−１，２，４，５，６，７−ヘキサヒドロ−３Ｈ−ピラゾロ［４，３−ｃ］ピリジン−３−オン；
５−エチル−２−フェニル−１，２，４，５，６，７−ヘキサヒドロ−３Ｈ−ピラゾロ［４，３−ｃ］ピリジン−３−オン；
２−フェニル−５−プロピル−１，２，４，５，６，７−ヘキサヒドロ−３Ｈ−ピラゾロ［４，３−ｃ］ピリジン−３−オン；
５−ブチル−２−フェニル−１，２，４，５，６，７−ヘキサヒドロ−３Ｈ−ピラゾロ［４，３−ｃ］ピリジン−３−オン；
５−（３−メチルブチル）−２−フェニル−１，２，４，５，６，７−ヘキサヒドロ−３Ｈ−ピラゾロ［４，３−ｃ］ピリジン−３−オン；
５−ベンジル−１，２，４，５，６，７−ヘキサヒドロ−３Ｈ−ピラゾロ［４，３−ｃ］ピリジン−３−オン（ＲＮ１０９３７５９−８７−５）。 In one embodiment of the compounds of the invention, the invention provides a pyrazolopiperidine derivative of formula (I):

[Wherein R ¹ is H; optionally substituted alkoxycarbonyl; optionally substituted C ₁ -C ₆ alkyl, eg, optionally substituted methyl (eg, Methyl), optionally substituted ethyl (eg 2-hydroxyethyl); optionally substituted C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkynyl Optionally substituted alkoxy; optionally substituted alkoxy C ₁ -C ₆ alkyl, eg, optionally substituted alkoxyethyl, eg, optionally substituted; Phenoxyethyl (eg, phenoxyethyl, 4-chlorophenoxyethyl), optionally substituted Optionally substituted aminoalkyl; optionally substituted acyl; optionally substituted aryl, eg, optionally substituted, methoxyethyl (eg, 2-methoxyethyl); optionally substituted aminoalkyl; optionally substituted acyl; Phenyl (for example, phenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 1-methoxyphenyl, 3-benzyloxyphenyl, 1-chlorophenyl, 2-chlorophenyl, 3- Chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 2-chloro-4-fluorophenyl, 3-fluorophenyl, 3-benzonitrile, 4-benzonitrile, 3-phenylacetamide); optionally substituted C ₁ -C ₆ alkylaryl; if More substituted aryl C ₁ optionally -C ₆ alkyl, for example by aryl methyl optionally substituted, for example by optionally substituted phenyl methyl (e.g., benzyl, 4-chlorobenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl); optionally substituted heteroaryl, such as optionally substituted benzodioxoyl (eg 1,3 benzodioxy) Sole-5-yl), optionally substituted benzothiazolyl (eg 2-methyl 1,3-benzothiazol-6-yl); optionally substituted C ₁ -C ₆ alkylheteroaryl Optionally substituted heteroaryl C ₁ -C ₆ alkyl, eg, Optionally substituted heteroarylmethyl, such as optionally substituted imidazo [1,2, a] pyridin-2-ylmethyl (eg, 2-imidazo [1,2, a] pyridine- 2-ylmethyl); optionally substituted C ₂ -C ₆ alkenyl aryl; optionally substituted aryl C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ Optionally substituted heteroaryl C ₂ -C ₆ alkenyl; optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted heterocycloalkyl, For example, an optionally substituted piperidine (eg, (eg, 1-methylpiperidine-4-i , 2-piperidin-1-ylethyl); optionally substituted C ₁ -C ₆ alkyl C ₃ -C ₈ -cycloalkyl; optionally substituted C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl; optionally substituted C ₁ -C ₆ alkyl heterocycloalkyl and optionally substituted heterocycloalkyl C ₁ -C ₆ alkyl, eg, optionally substituted Selected from optionally substituted heterocycloalkylethyl, for example morpholinylethyl (eg 2-morpholin-4-ylethyl) or optionally substituted piperidinethyl (eg 2-piperin-1-ylethyl) It is intended; ^{R 2} is, H; if _C 1 substituted by -C ₆ alkyl; situ Heteroaryl optionally optionally substituted; aryl which may be optionally substituted; optionally substituted C ₂ -C ₆ alkynyl optionally; substituted C ₂ -C ₆ alkenyl by For example, if the good pyridine alkyl optionally substituted, for example, optionally optionally substituted pyridine methyl (e.g., pyridin-3-yl - methyl); if substituted by C ₃ -C ₈ - Optionally substituted heterocycloalkyl; optionally substituted C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl; optionally substituted heterocycloalkyl C ₁ -C ₆ alkyl; optionally optionally substituted aryl _C 1 -C ₆ alkyl, for example Optionally, optionally substituted phenylalkyl, such as optionally substituted phenylmethyl (eg, benzyl) and optionally substituted heteroaryl C ₁ -C ₆ alkyl, eg, Selected from heteroarylmethyl optionally substituted by, for example, optionally substituted pyridinemethyl (eg, pyridin-3-ylmethyl); R ³ is —S (O) —R selected from cycloalkyl, optionally optionally substituted heterocycloalkyl and ^{-CR 5 R 6 R 7 - 4} , -S (O) 2 -R 4, when _C 3 substituted by -C ₈ R ⁴ is H; optionally substituted amino; optionally substituted C _1- C ₆ alkyl, eg, optionally substituted methyl (eg, methyl); optionally substituted C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkynyl An optionally substituted alkoxy; an optionally substituted alkoxy C ₁ -C ₆ alkyl, such as an optionally substituted aminoalkyl; an optionally substituted acyl; Optionally substituted aryl, eg, optionally substituted phenyl (eg, 4-methylphenyl); optionally substituted C ₁ -C ₆ alkylaryl; optionally substituted Optionally substituted aryl C ₁ -C ₆ alkyl, for example, optionally substituted aryl Optionally substituted heteroaryl; optionally substituted C ₁ -C ₆ alkyl heteroaryl; optionally substituted heteroaryl C ₁ -C ₆ alkyl; optionally substituted Optionally substituted C ₂ -C ₆ alkenyl aryl; optionally substituted aryl C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkenyl heteroaryl; optionally substituted Optionally substituted heteroaryl C ₂ -C ₆ alkenyl; optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted be optionally substituted; - C ₁ ~C ₆ alkyl _C 3 -C ₈ cycloalkyl There _C 3 -C ₈ - cycloalkyl _C 1 -C ₆ alkyl; optionally substituted _C 1 optionally -C ₆ alkyl heterocycloalkyl and optionally substituted heterocycloalkyl _C 1 optionally -C ₆ R ⁵ is selected from H and —CR ⁸ R ⁹ R ¹⁰ ; R ⁶ is selected from H and —CR ¹¹ R ¹² R ¹³ R ⁷ is selected from H, —CR ¹⁴ R ¹⁵ R ¹⁶ and —C (O) —R ¹⁷ ; R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^{14, R 15,} R ¹⁶ and R ¹⁷ are each independently, H; halogen; acyl which may be optionally substituted; when amino which may be optionally substituted by substituted Which may C ₁ -C ₆ alkyl, for example by optionally substituted alkoxyalkyl, for example alkoxymethyl (e.g., 2-phenoxymethyl); which may be optionally substituted C ₂ -C ₆ alkenyl; if Optionally substituted C ₂ -C ₆ alkynyl; optionally substituted aryl; optionally substituted C ₁ -C ₆ alkylaryl; optionally substituted aryl C ₁ -C ₆ alkyl; C ₁ which may be optionally substituted -C ₆ alkyl heteroaryl; optionally substituted also heteroaryl optionally optionally optionally substituted heteroaryl C ₁ -C ₆ alkyl ; If which may C ₂ even though -C ₆ alkenyl aryl substituted; optionally substituted Which may be aryl C ₂ -C ₆ alkenyl; optionally substituted; optionally substituted C ₂ -C ₆ alkenyl heteroaryl; optionally optionally substituted heteroaryl C ₂ -C ₆ alkenyl Optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C ₁ -C ₆ alkyl C ₃ -C ₈ -cycloalkyl; which may C ₃ even though -C 8 substituted by _- cycloalkyl C ₁ -C ₆ alkyl; when substituted, optionally C ₁ -C ₆ alkyl heterocycloalkyl and optionally substituted by heterocyclo Alkyl selected from C ₁ -C ₆ alkyl; —CR ⁸ R ⁹ R ¹⁰ , —CR ¹¹ R Each of ¹² R ¹³ or —CR ¹⁴ R ¹⁵ R ¹⁶ independently represents an optionally substituted aryl, such as an optionally substituted phenyl (eg, phenyl, 3-cyanophenyl, 4 -Cyanophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 1-chlorophenyl, 2-chlorophenyl, 4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-trifluoromethylphenyl, 4-methoxy Phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-cyanophenyl 4-benzyloxyphenyl, 4-methylsulfonylphenyl, 4-methylphenylacetamide, N-methyl Phenylamide); Optionally substituted heteroaryl, for example, optionally substituted pyridine (eg, pyridin-2-yl, pyridin-3-yl, 6-chloropyridin-3-yl); optionally substituted It may form an optionally substituted ring selected from optionally substituted C ₃ -C ₈ -cycloalkyl, or optionally substituted heterocycloalkyl. As well as tautomers, geometric isomers, optically active forms, pharmaceutically acceptable salts, and pharmaceutically active derivatives thereof, provided that the compound comprises the group consisting of Is not selected from.
5-methyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-ethyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-phenyl-5-propyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-butyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (3-methylbutyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-Benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one (RN1093759-87-5).

並びにその光学的に活性な形態、医薬的に許容される塩、および医薬的に活性な誘導体から選択され、ここで、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５、Ｒ^１６およびＲ^１７は、詳細な説明に定義したとおりのものである。 In certain embodiments, the present invention provides tautomers of compounds of formula (I), which tautomers include compounds of formula (Ia) and compounds of formula (Ib):

And optically active forms thereof, pharmaceutically acceptable salts, and pharmaceutically active derivatives, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in the detailed description.

In certain embodiments, provided are pyrazolopiperidine derivatives of formula (I) selected from the following group:
5-benzyl-2- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (2-chloro-4-fluorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- [3- (benzyloxy) phenyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (3-chlorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- [2- (4-chlorophenoxy) ethyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2,5-dibenzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-methoxybenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (3-chlorobenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,5-dimethoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- [2- (4-chlorophenoxy) ethyl] -5- (4-methoxybenzyl) octahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,4-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,5-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (2,4-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- [4- (Benzyloxy) benzyl] -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
5- (3-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (2-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (2-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (3-methoxyphenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile 5- (4-Chlorobenzyl) -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3 -ON;
5- (4-chlorobenzyl) -2- (3-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (2-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (3-methoxyphenyl) -5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-methoxybenzyl) -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Methoxybenzyl) -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3- on;
5- (4-chlorobenzyl) -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Methoxybenzyl) -2- (2-morpholin-4-ylethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
2- (1,3-Benzodioxol-5-yl) -5- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] Pyridin-3-one;
2- (1,3-Benzodioxol-5-yl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] Pyridin-3-one;
5- (2,4-dichlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (4-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-phenyl-5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-methoxybenzyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (3-methoxybenzyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-[(2-benzyl-3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzonitrile;
2- (2-hydroxyethyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (1,3-benzodioxol-5-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridine -5-yl] methyl} benzonitrile;
3- [5- (4-chlorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
5- (4-chlorobenzyl) -2- (2-hydroxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Chlorobenzyl) -2- (2-morpholin-4-ylethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
3a-benzyl-5- (4-chlorobenzyl) -2-methyl-2,3a, 4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (2-phenoxyethyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-Methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c ] Pyridin-5-yl] methyl} benzonitrile;
N- {4-[(3-oxo-2-phenyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] phenyl} acetamide ;
N-methyl-4-[(3-oxo-2-phenyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzamide;
4- [5- (4-chlorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
5- (methylsulfonyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-[(4-methylphenyl) sulfonyl] -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-hydroxyethyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
4-{[2- (4-Chlorophenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzonitrile ;
2- (1,3-benzodioxol-5-yl) -5- (3-chloro-4-fluorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 3-c] pyridin-3-one;
5- (3-Chloro-4-fluorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [ 4,3-c] pyridin-3-one;
4-{[2- (3-methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- [4- (methylsulfonyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 , 3-c] pyridin-3-one;
5- (4-Chlorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3- c] pyridin-3-one;
2-Benzyl-5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
3-{[2- (2-Methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c ] Pyridin-5-yl] methyl} benzonitrile;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
3-[(2-benzyl-3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzonitrile;
4-{[2- (4-Methoxyphenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
3-Fluoro-4-{[2- (2-methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4 , 3-c] pyridin-5-yl] methyl} benzonitrile;
2- (1,3-Benzodioxol-5-yl) -5- [4- (methylsulfonyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
2- (1,3-benzodioxol-5-yl) -5- [3- (trifluoromethyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 3-c] pyridin-3-one;
2- (3-methoxybenzyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-methoxybenzyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
2- (4-chlorophenyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
3- [3-oxo-5- (pyridin-3-ylmethyl) -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
4-{[3-oxo-2- (2-piperidin-1-ylethyl) -1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] Methyl} benzonitrile;
N- {3- [3-oxo-5- (pyridin-3-ylmethyl) -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] Phenyl} acetamide;
2- (2-fluorophenyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-Fluorophenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
5-[(6-Chloropyridin-3-yl) methyl] -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine -3-one;
N- {3- [5- (3-Chloro-4-fluorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl] phenyl} acetamide;
4-{[2- (4-Methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
5- (4-Chlorobenzyl) -2-methyl-3a- (pyridin-3-ylmethyl) -2,3a, 4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3 -ON;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- [3- (trifluoromethyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [ 4,3-c] pyridin-3-one;
5- (3-Chloro-4-fluorobenzyl) -2- (4-chlorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
3- [5- (3-Chloro-4-fluorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] Benzonitrile;
3- {3-oxo-5- [3- (trifluoromethyl) benzyl] -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl} Benzonitrile;
3- {5-[(6-chloropyridin-3-yl) methyl] -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl} benzonitrile;
2-Benzyl-5- (3-chloro-4-fluorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (4-Chlorophenyl) -5-[(6-chloropyridin-3-yl) methyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine 3-on;
5-[(6-Chloropyridin-3-yl) methyl] -2- (2-fluorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine -3-one;
5-[(6-Chloropyridin-3-yl) methyl] -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
2-Benzyl-5-[(6-chloropyridin-3-yl) methyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4- {5-[(6-chloropyridin-3-yl) methyl] -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl} benzonitrile;
2-Benzyl-5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
5- (2-Chlorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3- c] pyridin-3-one;
2-benzyl-5- (methylsulfonyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one; and 2- (imidazo [1,2 -A] pyridin-2-ylmethyl) -5-[(4-methylphenyl) sulfonyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3- on.

Compositions The present invention relates to medical disorders, particularly disorders mediated by NADPH oxidase, such as cardiovascular disorders or diseases, respiratory disorders or diseases, diseases or disorders affecting metabolism, skin disorders, bone disorders, neuroinflammation Disorders, neurodegenerative disorders, renal diseases, reproductive disorders, diseases or disorders affecting the eye and / or lens, medical conditions affecting the inner ear, inflammatory disorders or diseases, liver disease, pain, cancer, angiogenesis, angiogenesis Pharmaceutical agents or therapeutic agents and methods are provided as compositions for treating patients, preferably mammalian patients, most preferably human patients suffering from gastrointestinal conditions and / or gastrointestinal diseases or disorders.

  The pharmaceutical composition of the present invention may contain one or more pyrazolopiperidine derivatives in any form described herein. The composition of the present invention may further contain one or more pharmaceutically acceptable additional ingredients such as alum, stabilizer, antimicrobial agent, buffer, coloring agent, flavoring agent, adjuvant and the like.

  The compounds of the present invention are prepared in the form of pharmaceutical compositions and their unit dosages together with conventionally used adjuvants, carriers, diluents or excipients and are solid (eg tablets or filled capsules) ), Or all oral forms that can be used as liquids (eg, solutions, suspensions, emulsions, elixirs, or capsules filled with these) or for parenteral (including subcutaneous) applications Can be set in the form of a sterile solution for injection. Such pharmaceutical compositions and unit dosage forms thereof may contain ingredients in conventional proportions, with or without additional active compounds or ingredients, such unit dosage forms being It may contain any suitable effective amount of the active ingredient that meets the intended daily dosage range to be used. The composition of the present invention is preferably injectable.

  The compositions of the present invention may be liquid formulations, including but not limited to aqueous or oily suspensions, solutions, emulsions, syrups, and elixirs. Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles including buffers, suspending and dispersing agents, coloring agents, flavoring agents and the like. The composition may also be formulated as a dry product for reconstitution with water or other suitable vehicle prior to use. Such liquid formulations may contain additives, including but not limited to suspending agents, emulsifiers, non-aqueous vehicles and preservatives. Suspending agents include, but are not limited to, sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fat. Emulsifiers include, but are not limited to lecithin, sorbitan monooleate, and acacia. Non-aqueous vehicles include, but are not limited to, edible oil, almond oil, fractionated coconut oil, oily ester, propylene glycol, and ethyl alcohol. Preservatives include, but are not limited to, methyl p-hydroxybenzoate or propyl p-hydroxybenzoate, and sorbic acid. Additional materials and processing techniques, etc. are described in Remington's Pharmaceutical Sciences Part 5, 21st Edition, 2005, University of the Sciences in Philadelphia, Lippincott Williams. Embedded in the book.

  The solid composition of the present invention may be in the form of a tablet or medicinal drop formulated by conventional methods. For example, tablets and capsules for oral administration may contain conventional excipients, including but not limited to binders, fillers, lubricants, disintegrants, and wetting agents. Binders include, but are not limited to, syrup, acacia, gelatin, sorbitol, tragacanth, starch mucus and polyvinylpyrrolidone. Fillers include but are not limited to lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate, and sorbitol. Lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol, and silica. Disintegrants include, but are not limited to, potato starch and sodium starch glycolate. Wetting agents include, but are not limited to, sodium lauryl sulfate. The tablets may be coated by methods well known in the art.

  Injectable compositions are typically based on injectable sterile saline, phosphate buffered saline, or other injectable carriers known in the art.

  The composition of the present invention may be formulated as a suppository, which may contain a suppository base including but not limited to cocoa butter or glycerides. The compositions of the present invention may also be formulated for inhalation, including but not limited to forms such as solutions, suspensions, or emulsions that can be administered as dry powders, or dichlorodifluoromethane. Alternatively, it may be in the form of an aerosol using a propellant such as trichlorofluoromethane. . The compositions of the present invention may be formulated as transdermal formulations containing aqueous or non-aqueous vehicles including, but not limited to, creams, ointments, lotions, pastes, medical salves, patches or films.

  The compositions of the present invention may be formulated for parenteral administration by, but not limited to, injection or continuous infusion. Injectable preparations may be in the form of suspensions, solutions or emulsions of oily or aqueous vehicles, and contain formulations such as, but not limited to, suspensions, stabilizers, and dispersants. Also good. The composition may also be provided in powder form for reconstitution with a suitable vehicle such as, but not limited to, sterile water free of pathogenic bacteria.

  The compositions of the invention may be formulated as a depot preparation and administered by implantation or intramuscular injection. The composition may be formulated with a suitable polymeric or hydrophobic material (eg, as an acceptable emulsion in oil), ion exchange resin, or a poorly soluble derivative (eg, poorly soluble) Salt).

  The composition of the present invention may be formulated as a liposome preparation. The liposome preparation may contain liposomes that pass through the cells or stratum corneum of interest, fuse with the cell membrane, and deliver the contents of the liposomes to the cells. Other suitable formulations may use niosomes. Niosomes are lipid vesicles resembling liposomes, the membranes are mainly composed of nonionic lipids, and some forms of niosomes are effective in carrying compounds through the stratum corneum.

  The compounds of the invention can be administered in sustained release forms or can be administered from sustained release drug delivery systems. A description of representative sustained release materials can also be found in the materials included in Remington's Pharmaceutical Sciences.

Dosage Forms Compositions of the invention include, but are not limited to, oral, parenteral, sublingual, transdermal, rectal, transmucosal, topical, by inhalation, by buccal or nasal administration, or combinations thereof May be administered. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, and intraarticular. The composition of the present invention may also be administered in the form of an implant, which allows the composition to be released slowly and allows for slow controlled intravenous infusion. In preferred embodiments, the pyrazolopiperidine derivatives of the invention are administered intravenously or subcutaneously.

  The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention in any way.

  The dosage administered to an individual as a single dose or multiple doses depends on the pharmacokinetic characteristics, patient condition and characteristics (sex, age, weight, health status, height), degree of symptoms, current treatment, treatment Will vary depending on a variety of factors, including the frequency of and the desired effect.

In accordance with one embodiment of the present invention, the compounds of the present invention and pharmaceutical formulations thereof may be administered alone or in adjuncts useful for the treatment of cancer, such as conventional chemotherapy for solid tumors. Substances used to modulate the establishment of metastases, or substances used for hormone therapy, or other molecules that act by causing programmed cell death, such as drugs that stop the synthesis of pre-DNA molecule building blocks Selected from the category of, for example, methotrexate (Abitrexate®), fluorouracil (Adrucil®), hydroxyurea (Hydrea®), mercaptopurine (Purinethol®) Concomitant drugs such as D in the cell nucleus Concomitant drugs selected from the category of drugs that directly damage A, such as cisplatin (Platinol®), antibiotics-daunorubicin (Cerubidin®), doxorubicin (Adriamycin®), etoposide (VePesid) ®), eg, concomitant drugs selected from the category of drugs that affect the synthesis or destruction of mitotic spindles, eg vinblastine (Velban®), vincristine (Oncovin®) And may be administered in combination with paclitaxel (Taxol®).

  According to another embodiment of the invention, the compounds of the invention and pharmaceutical formulations thereof may be administered in combination with agents that target cell surface proteins (eg, gene transfer and reception of cytokine receptor chains). Cytotoxic administration targeting the body).

  According to another embodiment of the invention, the compounds of the invention and pharmaceutical formulations thereof may be administered in combination with radiation therapy.

  The invention encompasses administration of a compound of the invention or pharmaceutical formulation thereof, wherein the compound of the invention or pharmaceutical formulation thereof is another therapeutic regimen or adjuvant (eg, multiple dosages) useful in the treatment of cancer. Is administered to an individual in a therapeutically effective amount prior to (planning) or concurrently with or sequentially. The compound of the present invention or a pharmaceutical formulation thereof administered simultaneously with the above-mentioned adjuvant may be administered in the same composition or different compositions, and may be administered by the same administration route or different administration routes.

  In another specific embodiment, the compounds and methods of the invention are typically such that administration of the compounds of the invention is performed during or after chemotherapy, hormonal therapy, or radiation therapy, It is intended for use in the treatment of cancer.

  In another specific embodiment, the compounds and methods of the invention typically restore angiogenesis after planning chemotherapy, hormonal therapy, or radiation therapy, ie by providing blood supply and nutrition to the tumor tissue. It is envisioned for use in the treatment of cancer such that administration of a compound of the present invention is performed when tumor tissue responds to toxic challenge by induction of.

  In another embodiment, administration of a compound of the invention is performed after surgery to remove the solid tumor to prevent metastasis.

In certain embodiments, a patient of the invention is a patient suffering from a cardiovascular disorder or disease.

  In another embodiment, the patient of the present invention is a patient suffering from a respiratory disorder or disease.

  In another embodiment, a patient of the invention is a patient suffering from a disease or disorder that affects metabolism.

  In another embodiment, the patient of the present invention is a patient suffering from a skin disorder.

  In another embodiment, the patient of the present invention is a patient suffering from a bone disorder.

  In another embodiment, the patient of the present invention is a patient suffering from a neuroinflammatory disorder and / or a neurodegenerative disorder.

  In another embodiment, the patient of the present invention is a patient suffering from kidney disease.

  In another embodiment, the patient of the present invention is a patient suffering from a reproductive disorder.

  In another embodiment, a patient of the invention is a patient suffering from a disease or disorder affecting the eye and / or lens and / or a condition affecting the inner ear.

  In another embodiment, the patient of the present invention is a patient suffering from an inflammatory disorder or disease.

  In another embodiment, the patient of the present invention is a patient suffering from liver disease.

  In another embodiment, the patient of the present invention is a patient suffering from pain, eg, inflammatory pain.

  In another embodiment, the patient of the present invention is a patient suffering from cancer.

  In another embodiment, the patient of the invention suffers from angiogenesis or a condition that depends on angiogenesis.

  In another embodiment, the patient of the present invention is a patient suffering from an allergic disorder.

  In another embodiment, the patient of the present invention is a patient suffering from traumatic symptoms.

  In another embodiment, the patient of the present invention is a patient suffering from septic shock, hemorrhagic shock and anaphylactic shock.

  In another embodiment, the patient of the present invention is a patient suffering from a gastrointestinal disease or disorder.

In another embodiment of the invention, the invention provides a pyrazolopiperidine derivative of formula (I) for use as a medicament, wherein R ¹ is H; optionally substituted alkoxycarbonyl Optionally substituted C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkynyl; optionally substituted Optionally substituted alkoxy; optionally substituted alkoxy C ₁ -C ₆ alkyl; optionally substituted aminoalkyl; optionally substituted acyl; optionally substituted aryl; if C ₁ substituted by -C ₆ alkyl aryl; optionally substituted aryl C ₁ to ₆ alkyl; optionally, is heteroaryl C ₁ optionally -C ₆ alkyl optionally substituted; which may C ₁ -C ₆ alkylheteroaryl also be optionally substituted; heteroaryl optionally substituted optionally Optionally substituted C ₂ -C ₆ alkenyl aryl; optionally substituted aryl C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkenyl heteroaryl; optionally substituted Optionally substituted heteroaryl C ₂ -C ₆ alkenyl; optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted good _C 1 -C ₆ alkyl _C 3 -C ₈ - cycloalkyl; optionally substituted Which may be _C 3 -C ₈ - cycloalkyl _C 1 -C ₆ alkyl; if _C 1 substituted by -C ₆ alkyl heterocycloalkyl and optionally substituted heterocycloalkyl _C 1 optionally ~ It is those selected from C ₆ alkyl; ^{R 2} is, H; optionally substituted; which may _C 2 even though -C ₆ alkenyl optionally substituted; optionally substituted _C 1 -C ₆ alkyl Optionally substituted C ₂ -C ₆ alkynyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C ₃ -C ₈ -cycloalkyl; Optionally substituted heterocycloalkyl; optionally substituted C ₃ -C ₈ -cycloalkylC ₁ C ₆ alkyl; optionally substituted heterocycloalkyl C ₁ -C ₆ alkyl; optionally substituted aryl C ₁ -C ₆ alkyl and optionally substituted heteroaryl C _{1 to} C ₆ alkyl; R ³ is H, —S (O) —R ⁴ , —S (O) ₂ —R ⁴ , optionally substituted C _{3 to} C Selected from ₈ -cycloalkyl, optionally substituted heterocycloalkyl and —CR ⁵ R ⁶ R ⁷ ; R ⁴ is H; optionally substituted amino; optionally optionally substituted _C 1 -C ₆ alkyl; optionally optionally substituted _C 2 -C ₆ alkenyl; if _C 2 -C ₆ substituted by Arukini ; Optionally alkoxy substituted; optionally substituted alkoxy C ₁ optionally -C ₆ alkyl, for example by an amino alkyl optionally substituted; acyl which may be optionally substituted; Optionally substituted aryl; optionally substituted C ₁ -C ₆ alkylaryl; optionally substituted aryl C ₁ -C ₆ alkyl, eg, optionally substituted Optionally substituted heteroaryl; optionally substituted heteroaryl; optionally substituted C ₁ -C ₆ alkyl heteroaryl; optionally substituted heteroaryl C ₁ -C ₆ alkyl; location optionally; which may C ₂ -C ₆ alkenyl aryl optionally substituted optionally Which may be aryl C ₂ -C ₆ alkenyl; optionally substituted; optionally substituted C ₂ -C ₆ alkenyl heteroaryl; optionally optionally substituted heteroaryl C ₂ -C ₆ alkenyl Optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C ₁ -C ₆ alkyl C ₃ -C ₈ -cycloalkyl; which may C ₃ even though -C 8 substituted by _- cycloalkyl C ₁ -C ₆ alkyl; when substituted, optionally C ₁ -C ₆ alkyl heterocycloalkyl and optionally substituted by heterocyclo Alkyl selected from C ₁ -C ₆ alkyl; R ⁵ is H and —CR ⁸ R ⁹ R ^{1 0} is selected from a; ^{R 6} are those selected from H and ^{-CR 11 R 12 R 13; R} 7 ^{is, H, -CR 14 R 15 R} 16 and -C (O) - R ^17, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently H; halogen; An optionally substituted amino; an optionally substituted acyl; an optionally substituted C ₁ -C ₆ alkyl; an optionally substituted C ₂ -C ₆ alkenyl; Optionally substituted C ₂ -C ₆ alkynyl; optionally substituted aryl; optionally substituted C ₁ -C ₆ alkylaryl; optionally substituted Optionally substituted C ₁ -C ₆ alkyl; optionally substituted heteroaryl; optionally substituted C ₁ -C ₆ alkyl heteroaryl; optionally substituted heteroaryl C ₁ ~ C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl aryl; optionally substituted aryl C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ An optionally substituted heteroaryl C ₂ -C ₆ alkenyl; an optionally substituted C ₃ -C ₈ -cycloalkyl; an optionally substituted heterocycloalkyl; If _C 1 substituted by -C ₆ alkyl _C 3 -C ₈ - cycloalkyl If -C good C ₃ substituted by 8 _- cycloalkyl C ₁ -C ₆ alkyl; optionally optionally substituted C ₁ -C ₆ alkyl heterocycloalkyl and optionally may be substituted Is selected from heterocycloalkyl C ₁ -C ₆ alkyl; —CR ⁸ R ⁹ R ¹⁰ , —CR ¹¹ R ¹² R ¹³ or —CR ¹⁴ R ¹⁵ R ¹⁶ are each independently and optionally substituted An optionally substituted aryl; an optionally substituted heteroaryl; an optionally substituted C ₃ -C ₈ -cycloalkyl, or an optionally substituted heterocycloalkyl. An optionally substituted ring may be formed. ), And tautomers, geometric isomers, optically active forms, pharmaceutically acceptable salts, and pharmaceutically active derivatives thereof.

In a more particular embodiment, there is provided a pyrazolopiperidine derivative of formula (I) as defined above for use as a medicament. However, this compound is not selected from the group consisting of:
5-methyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-ethyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-phenyl-5-propyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-butyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (3-Methylbutyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one.

In a further embodiment, the present invention is ^{one wherein} R ¹ is selected from optionally substituted aryl and optionally substituted heteroaryl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in the detailed description. A pyrazolopiperidine derivative of the present invention is provided.

In another further embodiment, the invention provides that R ¹ is optionally substituted C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl; optionally substituted Optionally selected from C ₂ -C ₆ alkynyl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , Provided is a pyrazolopiperidine derivative of the present invention, wherein R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in the detailed description.

In another further embodiment, the invention selects R ¹ from optionally substituted aryl C ₁ -C ₆ alkyl, and optionally substituted heteroaryl C ₁ -C ₆ alkyl R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ And R ¹⁷ provides pyrazolopiperidine derivatives of the present invention, wherein R ¹⁷ is as defined in the detailed description.

In another further embodiment, the invention relates to wherein R ¹ is optionally substituted heterocycloalkyl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ provide a pyrazolopiperidine derivative of the present invention, as defined in the detailed description. .

In another further embodiment, the invention shows that R ¹ is optionally substituted heterocycloalkyl C ₁ -C ₆ alkyl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , The pyr of the invention wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in the detailed description. Zolopiperidine derivatives are provided.

In another further embodiment, the invention shows that R ¹ is optionally substituted alkoxy C ₁ -C ₆ alkyl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^7. , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in the detailed description, pyrazolopiperidines of the present invention Derivatives are provided.

In another further embodiment, the invention relates to wherein R ² is H; R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ provide a pyrazolopiperidine derivative of the present invention, as defined in the detailed description.

In another further embodiment, the invention selects R ² from optionally substituted aryl C ₁ -C ₆ alkyl, and optionally substituted heteroaryl C ₁ -C ₆ alkyl R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ And R ¹⁷ provides pyrazolopiperidine derivatives of the present invention, wherein R ¹⁷ is as defined in the detailed description.

In another further embodiment, the invention relates to R ³ being —CR ⁵ R ⁶ R ⁷ ; R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^11. , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ provide pyrazolopiperidine derivatives of the present invention, as defined in the detailed description.

In another further embodiment, the invention provides that R ³ is —CR ⁵ R ⁶ R ⁷ ; R ⁵ and R ⁶ are H; R ⁷ is —CR ¹⁴ R ¹⁵ R ¹⁶ ; R ¹ , Provided is a pyrazolopiperidine derivative of the present invention, wherein R ² , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in the detailed description.

In another further embodiment, the present invention is, ^{R 3} is located at the ^{-CR 5 R 6 R 7; R} 5 and ^{R 6} be H; ^{R 7} is located in the ^{-CR 14 R 15 R 16; -CR} 14 R ¹⁵ R ¹⁶ forms a ring selected from optionally substituted aryl and optionally substituted heteroaryl; R ¹ and R ² as defined in the detailed description There is provided a pyrazolopiperidine derivative of the present invention.

In another embodiment, the invention provides a pyrazolo of the invention, wherein R ³ is S (O) ₂ —R ⁴ ; and R ¹ , R ^2, and R ⁴ are as defined in the detailed description. Piperidine derivatives are provided.

In another further embodiment, the present invention is, ^{R 3} is S _(O) 2 -R ^4, and ^{R 4} is optionally substituted _C 1 -C ₆ alkyl; optionally substituted Selected from optionally C ₂ -C ₆ alkenyl, and optionally substituted C ₂ -C ₆ alkynyl; R ¹ and R ² are as defined in the detailed description. The pyrazolopiperidine derivatives of the present invention are provided.

In another further embodiment, the invention provides that R ³ is S (O) ₂ -R ⁴ , and R ⁴ is optionally substituted aryl, and optionally substituted hetero it is those selected from aryl; R ¹ and R ² are those as defined in the detailed description provides a pyrazolo piperidine derivative of the present invention.

In another embodiment, the present invention affects cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammation and / or neurodegenerative disorders, renal diseases, reproductive disorders, eyes and / or lenses. Diseases affecting and / or conditions affecting the inner ear, inflammatory disorders, liver disease, pain, cancer, allergic disorders, traumatic symptoms, septic shock, hemorrhagic shock and anaphylactic shock, gastrointestinal disorders, angiogenesis, For preparing a pharmaceutical composition for treating or preventing a disease or condition selected from angiogenesis dependent conditions and other diseases and disorders related to reducing nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) A pyrazolopiperidine derivative of the formula (I), wherein R ¹ is H; Optionally substituted C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkynyl; Optionally substituted alkoxy; optionally substituted alkoxy C ₁ -C ₆ alkyl; optionally substituted aminoalkyl; optionally substituted acyl; optionally substituted Optionally substituted aryl; optionally substituted C ₁ -C ₆ alkylaryl; optionally substituted aryl C ₁ -C ₆ alkyl; optionally substituted heteroaryl; It is optionally substituted; which may C ₁ -C ₆ alkyl heteroaryl optionally substituted by There heteroaryl C ₁ -C ₆ alkyl; may be optionally substituted; optionally substituted C ₂ -C ₆ alkenyl aryl; optionally optionally substituted aryl C ₂ -C ₆ alkenyl C ₂ -C ₆ alkenyl heteroaryl; optionally C ₃ substituted optionally -C 8 _- cycloalkyl; optionally heteroaryl C ₂ -C ₆ alkenyl optionally substituted substituted optionally Optionally substituted C ₁ -C ₆ alkyl optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl ; optionally is optionally substituted C ₁ -C ₆ alkyl heterocycloalkyl and optionally substituted Even though is one selected from Good heterocycloalkyl C ₁ -C ₆ alkyl; R ² is, H; may be optionally substituted; optionally substituted C ₁ -C ₆ alkyl C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkynyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted good C ₃ -C 8 _- cycloalkyl; _-; optionally substituted cycloalkyl C ₁ -C ₆ alkyl C ₃ which may be optionally substituted -C 8; if good heterocycloalkyl optionally substituted by Optionally heterocycloalkyl C ₁ -C ₆ alkyl; optionally substituted aryl C ₁ -C ₆ alkyl and Optionally selected from heteroaryl C ₁ -C ₆ alkyl; R ³ is H, —S (O) —R ⁴ , —S (O) ₂ —R ⁴ , ~C good _C 3 substituted by ₈ - cycloalkyl, optionally are those selected from the good heterocycloalkyl and ^-CR 5 ^R 6 ^{R 7} optionally substituted; ^{R 4} is, H; if Optionally substituted amino; optionally substituted C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl; optionally substituted C _2- C ₆ alkynyl; optionally alkoxy substituted; optionally optionally substituted alkoxy C ₁ -C ₆ alkyl, for example by amino which may be substituted Alkyl; aryl which may be optionally substituted; optionally optionally substituted C ₁ -C ₆ alkyl aryl; optionally substituted optionally also substituted acyl substituted aryl C ₁ be optionally substituted - C ₆ alkyl, eg, optionally substituted arylmethyl; optionally substituted heteroaryl; optionally substituted C ₁ -C ₆ alkyl heteroaryl; optionally substituted Optionally substituted heteroaryl C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl aryl; optionally substituted aryl C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkenyl heteroaryl; optionally substituted hetero Aryl C ₂ -C ₆ alkenyl; optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C ₁ -C ₆ Alkyl C ₃ -C ₈ -cycloalkyl; optionally substituted C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl; optionally substituted C ₁ -C ₆ alkyl heterocycloalkyl And optionally substituted heterocycloalkyl C ₁ -C ₆ alkyl; R ⁵ is selected from H and —CR ⁸ R ⁹ R ¹⁰ ; R ⁶ is are those selected from H and ^{-CR 11 R 12 R 13; R} 7 ^{is, H, -CR 14 R 15 R} 16 and -C (O) - Are those selected from the ^{17; R 8, R 9,} R 10, R 11, R 12, R 13, R 14, R 15, R 16 and ^{R 17} are each independently, H; halogen; if Optionally substituted amino; optionally substituted acyl; optionally substituted C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl; Optionally substituted C ₂ -C ₆ alkynyl; optionally substituted aryl; optionally substituted C ₁ -C ₆ alkylaryl; optionally substituted aryl C ₁ -C ₆ alkyl; C ₁ which may be optionally substituted -C ₆ alkyl heteroaryl; heteroaryl substituted optionally if Optionally substituted C ₂ -C ₆ alkenyl aryl, optionally; optionally optionally substituted aryl C ₂ -C ₆ alkenyl; optionally further substituted heteroaryl C ₁ -C ₆ alkyl Optionally substituted C ₂ -C ₆ alkenyl heteroaryl; optionally substituted heteroaryl C ₂ -C ₆ alkenyl; optionally substituted C ₃ -C ₈ -cycloalkyl; is C ₁ -C ₆ alkyl C ₃ optionally -C optionally substituted 8 _- cycloalkyl; optionally substituted heterocycloalkyl by which may be optionally substituted C ₃ -C 8 _- cycloalkyl C ₁ -C ₆ alkyl; optionally substituted _C 1 optionally -C ₆ alkyl heterocycloalkyl And optionally it is selected from a by heterocycloalkyl _C 1 optionally -C ₆ alkyl ^{substituted; -CR 8 R 9 R 10,} -CR 11 R 12 R 13 or ^-CR 14 ^R 15 ^{R 16} is Each independently an optionally substituted aryl; an optionally substituted heteroaryl; an optionally substituted C ₃ -C ₈ -cycloalkyl, or an optionally substituted It may form an optionally substituted ring selected from optionally heterocycloalkyl. ), And tautomers, geometric isomers, optically active forms, pharmaceutically acceptable salts, and pharmaceutically active derivatives thereof.

In another embodiment, the present invention affects cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammation and / or neurodegenerative disorders, renal diseases, reproductive disorders, eyes and / or lenses. Diseases affecting and / or conditions affecting the inner ear, inflammatory disorders, liver disease, pain, cancer, allergic disorders, traumatic symptoms, septic shock, hemorrhagic shock and anaphylactic shock, gastrointestinal disorders, angiogenesis, For treating or preventing a disease or condition selected from angiogenesis dependent conditions and other diseases and disorders associated with reducing nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) A pyrazolopiperidine derivative wherein R ¹ is H; an optionally substituted alkoxycarbonyl; Optionally substituted C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkynyl; optionally substituted Optionally substituted alkoxy; optionally substituted alkoxy C ₁ -C ₆ alkyl; optionally substituted aminoalkyl; optionally substituted acyl; optionally substituted Optionally substituted C ₁ -C ₆ alkylaryl; optionally substituted aryl C ₁ -C ₆ alkyl; optionally substituted heteroaryl; optionally substituted Optionally C ₁ -C ₆ alkyl heteroaryl; optionally substituted heteroaryl C _{1 to} C ₆ alkyl; optionally substituted C _{2 to} C ₆ alkenyl aryl; optionally substituted aryl C _{2 to} C ₆ alkenyl; optionally substituted C _{2 to} C ₆ alkenyl heteroaryl; if heteroaryl optionally substituted by C ₂ -C ₆ alkenyl; C ₃ which may be optionally substituted -C 8 _- cycloalkyl; optionally may heterocycloalkyl optionally substituted Optionally substituted C ₁ -C ₆ alkyl C ₃ -C ₈ -cycloalkyl; optionally substituted C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl; optionally substituted It is C ₁ optionally -C ₆ alkyl heterocycloalkyl and optionally substituted optionally hetero Are those selected from a cycloalkyl _C 1 -C ₆ alkyl; ^{R 2} is, H; if _C 1 substituted by -C ₆ alkyl; when _C 2 substituted by -C ₆ Optionally substituted C ₂ -C ₆ alkynyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl; optionally substituted heterocyclo Alkyl C ₁ -C ₆ alkyl; optionally substituted aryl C ₁ -C ₆ alkyl and optionally substituted Optionally selected from heteroaryl C ₁ -C ₆ alkyl; R ³ is H, —S (O) —R ⁴ , —S (O) ₂ —R ⁴ , optionally substituted. C ₃ -C ₈ -cycloalkyl, optionally selected from heterocycloalkyl and —CR ⁵ R ⁶ R ⁷ ; R ⁴ is H; optionally substituted Optionally substituted; optionally substituted C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkynyl; the alkoxy optionally substituted; optionally substituted alkoxy C ₁ optionally -C ₆ alkyl, for example, an amino alkyl which may be optionally substituted; optionally C ₁ which may be optionally substituted -C ₆ alkyl aryl; aryl which may be optionally substituted; conversion is also an acyl optionally optionally substituted aryl C ₁ -C ₆ alkyl, For example, an optionally substituted arylmethyl; an optionally substituted heteroaryl; an optionally substituted C ₁ -C ₆ alkylheteroaryl; an optionally substituted hetero Aryl C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl aryl; optionally substituted aryl C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkenyl heteroaryl; if heteroaryl _C 2 may be substituted by -C ₆ Alkenyl; optionally C ₃ substituted optionally -C 8 _- cycloalkyl; if good heterocycloalkyl optionally substituted by; C ₁ -C ₆ alkyl C ₃ which may be optionally substituted -C ₈ - cycloalkyl; if -C good C ₃ substituted by 8 _- cycloalkyl C ₁ -C ₆ alkyl; optionally substituted, optionally C ₁ -C ₆ alkyl heterocycloalkyl and optionally substituted Optionally selected from heterocycloalkyl C ₁ -C ₆ alkyl; R ⁵ is selected from H and —CR ⁸ R ⁹ R ¹⁰ ; R ⁶ is H and —CR ¹¹ R ¹² is selected from R ¹³ ; R ⁷ is selected from H, —CR ¹⁴ R ¹⁵ R ¹⁶ and —C (O) —R ¹⁷ R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently H; halogen; optionally substituted Optionally substituted acyl; optionally substituted acyl; optionally substituted C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkynyl; optionally substituted aryl; optionally substituted C ₁ -C ₆ alkylaryl; optionally substituted aryl C ₁ -C ₆ alkyl ; it is optionally substituted; optionally heteroaryl optionally substituted; optionally substituted C ₁ optionally -C ₆ alkylheteroaryl Heteroaryl C ₁ -C ₆ alkyl; may be optionally substituted; optionally substituted C ₂ -C ₆ alkenyl aryl; optionally optionally substituted aryl C ₂ -C ₆ alkenyl C ₂ -C ₆ alkenyl heteroaryl; optionally C ₃ substituted optionally -C 8 _- cycloalkyl; optionally heteroaryl C ₂ -C ₆ alkenyl optionally substituted substituted optionally Optionally substituted C ₁ -C ₆ alkyl optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl ; optionally substituted, optionally C ₁ -C ₆ alkyl heterocycloalkyl and optionally substituted Is is selected from a good heterocycloalkyl _C 1 -C ₆ alkyl ^{optionally; -CR 8 R 9 R 10,} -CR 11 R 12 R 13 or ^-CR 14 ^R 15 ^{R 16} are each independently Optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C ₃ -C ₈ -cycloalkyl, or optionally substituted hetero It may form an optionally substituted ring selected from cycloalkyl. ), And tautomers, geometric isomers, optically active forms, pharmaceutically acceptable salts, and pharmaceutically active derivatives thereof.

The compounds of the present invention include in particular those selected from the following group:
5-benzyl-2- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (2-chloro-4-fluorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- [3- (benzyloxy) phenyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-chloro-4-fluorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (3-chlorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- [2- (4-chlorophenoxy) ethyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2,5-dibenzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-methoxybenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (3-chlorobenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,5-dimethoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- [2- (4-chlorophenoxy) ethyl] -5- (4-methoxybenzyl) octahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,4-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,5-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (2,4-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- [4- (Benzyloxy) benzyl] -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
5- (3-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (2-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (2-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (3-methoxyphenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
5- (4-Chlorobenzyl) -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3- on;
5- (4-chlorobenzyl) -2- (3-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (2-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (3-methoxyphenyl) -5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-methoxybenzyl) -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Methoxybenzyl) -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3- on;
5- (4-chlorobenzyl) -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Methoxybenzyl) -2- (2-morpholin-4-ylethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
2- (1,3-Benzodioxol-5-yl) -5- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] Pyridin-3-one;
2- (1,3-Benzodioxol-5-yl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] Pyridin-3-one;
5- (2,4-dichlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (4-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-phenyl-5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-methoxybenzyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (3-methoxybenzyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-[(2-benzyl-3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzonitrile;
2- (2-hydroxyethyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (1,3-benzodioxol-5-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridine -5-yl] methyl} benzonitrile;
3- [5- (4-chlorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
5- (4-chlorobenzyl) -2- (2-hydroxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Chlorobenzyl) -2- (2-morpholin-4-ylethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
3a-benzyl-5- (4-chlorobenzyl) -2-methyl-2,3a, 4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (2-phenoxyethyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-Methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c ] Pyridin-5-yl] methyl} benzonitrile;
N- {4-[(3-oxo-2-phenyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] phenyl} acetamide ;
N-methyl-4-[(3-oxo-2-phenyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzamide;
4- [5- (4-chlorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
5- (methylsulfonyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-[(4-methylphenyl) sulfonyl] -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-hydroxyethyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
4-{[2- (4-Chlorophenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzonitrile ;
2- (1,3-benzodioxol-5-yl) -5- (3-chloro-4-fluorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 3-c] pyridin-3-one;
5- (3-Chloro-4-fluorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [ 4,3-c] pyridin-3-one;
4-{[2- (3-methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- [4- (methylsulfonyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 , 3-c] pyridin-3-one;
5- (4-Chlorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3- c] pyridin-3-one;
2-Benzyl-5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
3-{[2- (2-Methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c ] Pyridin-5-yl] methyl} benzonitrile;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
3-[(2-benzyl-3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzonitrile;
4-{[2- (4-Methoxyphenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
3-Fluoro-4-{[2- (2-methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4 , 3-c] pyridin-5-yl] methyl} benzonitrile;
2- (1,3-Benzodioxol-5-yl) -5- [4- (methylsulfonyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
2- (1,3-benzodioxol-5-yl) -5- [3- (trifluoromethyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 3-c] pyridin-3-one;
2- (3-methoxybenzyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-methoxybenzyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
2- (4-chlorophenyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
3- [3-oxo-5- (pyridin-3-ylmethyl) -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
4-{[3-oxo-2- (2-piperidin-1-ylethyl) -1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] Methyl} benzonitrile;
N- {3- [3-oxo-5- (pyridin-3-ylmethyl) -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] Phenyl} acetamide;
2- (2-fluorophenyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-Fluorophenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
5-[(6-Chloropyridin-3-yl) methyl] -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine -3-one;
N- {3- [5- (3-Chloro-4-fluorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl] phenyl} acetamide;
4-{[2- (4-Methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
5- (4-Chlorobenzyl) -2-methyl-3a- (pyridin-3-ylmethyl) -2,3a, 4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3 -ON;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- [3- (trifluoromethyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [ 4,3-c] pyridin-3-one;
5- (3-Chloro-4-fluorobenzyl) -2- (4-chlorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
3- [5- (3-Chloro-4-fluorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] Benzonitrile;
3- {3-oxo-5- [3- (trifluoromethyl) benzyl] -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl} Benzonitrile;
3- {5-[(6-chloropyridin-3-yl) methyl] -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl} benzonitrile;
2-Benzyl-5- (3-chloro-4-fluorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (4-Chlorophenyl) -5-[(6-chloropyridin-3-yl) methyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine 3-on;
5-[(6-Chloropyridin-3-yl) methyl] -2- (2-fluorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine -3-one;
5-[(6-Chloropyridin-3-yl) methyl] -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
2-Benzyl-5-[(6-chloropyridin-3-yl) methyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4- {5-[(6-chloropyridin-3-yl) methyl] -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl} benzonitrile;
2-Benzyl-5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
5- (2-Chlorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3- c] pyridin-3-one;
2-benzyl-5- (methylsulfonyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one; and 2- (imidazo [1,2 -A] pyridin-2-ylmethyl) -5-[(4-methylphenyl) sulfonyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3- on.

  In another embodiment, the present invention affects cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammation and / or neurodegenerative disorders, renal diseases, reproductive disorders, eyes and / or lenses. Diseases affecting and / or conditions affecting the inner ear, inflammatory disorders, liver disease, pain, cancer, allergic disorders, traumatic symptoms, septic shock, hemorrhagic shock and anaphylactic shock, gastrointestinal disorders, angiogenesis, Methods are provided for treating patients suffering from a disease or condition selected from angiogenesis-dependent conditions and other diseases and disorders associated with reducing nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase). This method comprises administering a compound of formula (I) to a patient in need thereof.

  In another embodiment, the invention provides a method of inhibiting angiogenesis in a patient in need thereof, the method comprising administering to a patient in need thereof a compound of formula (I) angiogenesis. There is provided a method comprising administering at an inhibitory dosage.

  In another embodiment, the present invention provides a method of inhibiting tumor neovascularization by inhibiting tumor angiogenesis according to the methods of the present invention. Similarly, the present invention provides a method for inhibiting tumor growth by implementing a method for inhibiting angiogenesis.

  In certain embodiments, the compounds and methods of the present invention are directed to the treatment of tumor tissue in patients with cancer, such as tumors, solid tumors, metastases, cancer, melanoma, skin cancer, breast cancer, hemangioma, or angiofibroma. Angiogenesis that is inhibited is neovascularization of tumor tissue where neovascularization of the tumor tissue is present. Exemplary solid tumor tissues that can be treated by the compounds and methods of the present invention include, but are not limited to, skin, melanoma, lung, pancreas, breast, colon, larynx, ovary, prostate, colorectal, head, neck , Tumors of tissues such as testicles, lymphocytes, bone marrow, bone, sarcoma, kidney, sweat gland. A further example of a cancer that is to be treated is glioblastoma.

  In another specific embodiment, the compounds and methods of the invention contemplate use for the treatment of inflamed tissue, and the angiogenesis that is inhibited is angiogenesis of inflamed tissue in which neovascularization of the inflamed tissue is present It is. In this case, the compounds and methods of the present invention envision suppression of angiogenesis in arthritic tissues (eg, rheumatoid arthritis patients, immune inflammatory or non-immune inflammatory tissues, psoriatic tissues, etc.).

  In some embodiments, the present invention contemplates inhibiting tissue angiogenesis. The degree of angiogenesis in the tissue, and thus the degree of suppression achieved by the present invention, can be assessed by various methods as described herein.

  According to one embodiment of the invention, the disease or condition is cancer.

  According to one embodiment of the invention, the compounds of the invention are administered in combination with adjuvants useful for the treatment of cancer.

  According to one embodiment of the invention, the compounds of the invention are administered in combination with radiation therapy.

  In another embodiment, the present invention provides a pharmaceutical composition comprising at least one pyrazolopiperidine derivative of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient thereof. To do.

  The compounds of the invention are named according to the IUPAC standard used in the ACD / Name program (product version 10.1).

  The compounds of the present invention include compounds of formula (I), tautomers, geometric isomers, enantiomers, optically active forms such as diastereomers, racemates, and pharmaceutically acceptable compounds thereof. Containing salt. The derivatives exemplified in this invention may be prepared from readily available starting materials using the following general methods and procedures. Even if typical or preferred experimental conditions (ie reaction temperature, reaction time, moles of reagents, moles of solvent, etc.) are given, other experimental conditions can be used unless otherwise stated. Will be understood. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art using routine optimization procedures.

  References cited herein are hereby incorporated by reference in their entirety. The present invention is not to be limited in scope by the specific embodiments described herein, which are intended to be merely illustrative of individual aspects of the invention and are functional. All equivalent methods and elements are within the scope of the invention. Indeed, various modifications in addition to those shown and described herein will become apparent to those skilled in the art from the following description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

  While describing the present invention, the following examples are presented for purposes of illustration and not limitation.

Synthesis of Compounds of the Invention The novel derivatives of formula (I) can be prepared from readily available starting materials using the following general methods and procedures. Although typical or preferred experimental conditions (ie, reaction temperature, reaction time, moles of reagents, moles of solvent, etc.) are given, other experimental conditions can be used unless otherwise stated. Will be understood. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art using routine optimization procedures.

A general synthetic method for obtaining a compound of formula (I) is shown in Scheme 1 below.

Following the synthesis protocol outlined in Scheme 1 above, a pyrazolopiperidine derivative of formula (I), wherein the substituents R ¹ , R ² and R ³ are as defined above, is custom-made or commercially available. From the substituted piperidine derivative of formula (V) in three chemical steps: an alkyl halide or sulfonyl chloride of formula (IV), an alkyl halide of formula (VI), and a hydrazine derivative of formula (II). Good. In a more specific method, a piperidine derivative of formula (V) (wherein R ¹⁸ is as defined above) is added to a suitable base (eg triethylamine, di-isopropylethylamine, hydrogenation as base). Alkylation in the presence of sodium or potassium carbonate) in a suitable solvent (eg dichloromethane, N, N-dimethylformamide or tetrahydrofuran) at room temperature, by conventional heating methods or using microwave techniques Treatment with an agent (eg, alkyl chloride, alkyl bromide, alkyl iodide, or alkyl mesylate) or sulfonyl chloride (wherein R ³ is as defined above). The intermediate compound of formula (III) is further reacted with a hydrazine derivative of formula (II), wherein R ¹ is as defined above. After cyclization, preferably in a protic solvent, in the presence of a base (sodium methanolate, sodium isopropanolate, etc.) using standard reflux conditions familiar to those skilled in the art as shown in Scheme 1. A pyrazolo derivative of formula (Ib) (ie a compound of formula (I) wherein R ² is H) is isolated. In the next step, the intermediate compound of formula (III) is converted to a suitable solvent (for example, sodium hydride as the base) in the presence of a suitable base (for example, sodium hydride as the base), depending on the inherent reactivity of the compound of formula (VI). For example, alkylating agents of formula (VI) such as alkyl chloride, alkyl bromide, alkyl iodide, or alkyl mesylate in N, N-dimethylformamide) at room temperature or by conventional heating methods. And R ³ is as defined above). The resulting intermediate compound of formula (VII) is further reacted with a hydrazine derivative of formula (II), wherein R ¹ is as defined above. Preferably, after cyclization in a protic solvent in the presence of an acid such as acetic acid, for example, using standard reflux conditions familiar to those skilled in the art as shown in Scheme 1, the pyrazolo of formula (I) The derivative is isolated.

The following abbreviations refer to the following definitions, respectively.
Å (angstrom), min (minute), h (hour), g (gram), MHz (megahertz), mL (milliliter), mm (millimeter), mmol (mmol), mM (mmol concentration), ng (nanogram) , Nm (nanometer), BLM (bleomycin), BSA (bovine serum albumin), DCF (2,7-dichlorodihydrofluorescein), DCM (dichloromethane), DMSO (dimethylsulfoxide), DMF (N, N-dimethylformamide) , DAPI (4,6 diamidino-2-phenylindole), DPI (diphenyl-iodonium), EDTA (ethylenediaminetetraacetic acid), EGF (epidermal growth factor), EtOAc (ethyl acetate), FCS (fetal bovine serum), HBSS ( Hank buffered salt solution), HPLC (high Speed liquid _{chromatography), H 2 DCF-DA (} 2 ', 7'- dichloro-dihydro fluorescein diacetate), MEM (2-methoxyethoxymethyl), MS (mass spectrometry), NADPH (reduced nicotinamide adenine dinucleotide Diphosphate), NBT (nitroblue tetrazolium), NMR (nuclear magnetic resonance), PBS (phosphate buffered saline), TFA (trifluoroacetic acid), TGF-β (tumor growth factor beta), ROS (reactive oxygen species) ), SOD (superoxide dismutase), SPA (scintillation proximity assay), TLC (thin layer chromatography), UPLC (ultra high performance liquid chromatography), UV (ultraviolet).

  If the above series of general synthetic methods cannot be applied to obtain the intermediates necessary for the synthesis of compounds of formula (I) and / or compounds of formula (I), those skilled in the art will know A suitable preparation method may be used. In general, the suitable synthetic route for any individual compound of formula (I) will vary depending on the particular substituents of each molecule, the availability of the required intermediates. Again, such factors will be understood by those skilled in the art. For all protection and deprotection methods, see Philip J. et al. Kocienski's “Protecting Groups”, Georg Thieme Verlag Stuttgart, 2005 and Theodora W. Greene and Peter G. M.M. See Wuts' "Protective Groups in Organic Synthesis", Wiley Interscience, 4th edition, 2006.

  The compounds of the invention can be crystallized by evaporating an appropriate solvent and isolated in association with solvent molecules. Pharmaceutically acceptable acid addition salts of compounds of formula (I) containing a basic center may be prepared by conventional methods. For example, a solution of the free base may be isolated by treatment with an appropriate acid, undiluted or in an appropriate solution, and filtering the resulting salt or evaporating the reaction solvent under vacuum. Pharmaceutically acceptable base addition salts may be obtained in a similar manner by treating a solution of the compound of formula (I) with a suitable base. Both types of salts may be made or may be interconverted using ion exchange resin technology.

  The invention will now be illustrated by several examples, which should not be construed as limiting the scope of the invention.

The HPLC, NMR and MS data given in the examples described below were obtained as follows: HPLC: Column Waters Symmetry C8 50 × 4.6 mm, Conditions: MeCN / H ₂ O, 5 to 100% ( 8 min), maximum plot 230-400 nm; mass spectrum: PE-SCIEX API 150 EX (APCI and ESI), LC / MS spectrum: Waters ZMD (ES); ¹ H-NMR: Bruker DPX-300 MHz.

Preparative HPLC purification is HPLC with Prep Nova-Pak® HR C186 μm 60 mm, 40 × 30 mm (up to 100 mg) column, or XTerra® Prep MS C8, 10 μm, 50 × 300 mm (up to 1 g). Performed on a Waters Prep LC 4000 System. All purifications were performed with a gradient of MeCN / H ₂ O 0.09% TFA; UV detection at 254 nm and 220 nm; flow rate 20 mL / min (up to 50 mg). TLC analysis was performed on Merck Precoated 60 F ₂₅₄ plates. Purification by flash chromatography was carried out using a SiO ₂ support and using a mixture of cyclohexane / EtOAc or DCM / MeOH as eluent.

Example 1: 2-Phenyl-5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one (43) Formation of (Compound Ib, Scheme 1)

無水ＣＨ_３ＣＮ５．０ｍＬ中で、１−メチル−４−オキソピペリジン−３−カルボキシレート塩酸塩（市販、ＡＢＣＲ）０．２００ｇ（１．０３４ｍｍｏｌ）と、ジイソプロピルエチルアミン０．５４ｍＬ（３．１０２ｍｍｏｌ）と、ヨウ化ナトリウム０．１５５ｇ（１．０３４ｍｍｏｌ）と、３−（クロロメチル）ピリジン塩酸塩０．１７０ｇ（１．０３４ｍｍｏｌ）とを８０℃で撹拌した。反応をＨＰＬＣおよびＵＰＬＣ−ＭＳで測定した。８０℃で１時間経過後、不溶性無機物質を濾別し、濾液を真空下で濃縮し、黄色がかった残渣を得た。この残渣をＣＨ_２Ｃｌ_２に溶解し、塩水、Ｈ_２Ｏで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮して、純粋な４−オキソ−１−（ピリジン−３−イルメチル）ピペリジン−３−カルボン酸メチル（０．２５７ｇ、１．０３４ｍｍｏｌ、定量的収率）を得た。この生成物をさらに操作することなく次の工程で使用した。 (A) methyl 4-oxo-1- (pyridin-3-ylmethyl) piperidine-3-carboxylate (compound of formula (III), scheme 1)

In 5.0 mL of anhydrous CH ₃ CN, 0.200 g (1.034 mmol) of 1-methyl-4-oxopiperidine-3-carboxylate hydrochloride (commercially available, ABCR) and 0.54 mL (3.102 mmol) of diisopropylethylamine , 0.155 g (1.034 mmol) of sodium iodide and 0.170 g (1.034 mmol) of 3- (chloromethyl) pyridine hydrochloride were stirred at 80 ° C. The reaction was measured by HPLC and UPLC-MS. After 1 hour at 80 ° C., the insoluble inorganic material was filtered off and the filtrate was concentrated in vacuo to give a yellowish residue. This residue was dissolved in CH ₂ Cl ₂ , washed with brine, H ₂ O, dried over Na ₂ SO ₄ and concentrated in vacuo to give pure 4-oxo-1- (pyridin-3-ylmethyl) Methyl piperidine-3-carboxylate (0.257 g, 1.034 mmol, quantitative yield) was obtained. This product was used in the next step without further manipulation.

(B) 2-phenyl-5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one (formula (Ib ), Scheme 1)
In a three-necked flask under nitrogen atmosphere in EtOH 3.50 mL with 0.257 g (1.034 mmol) of methyl 4-oxo-1- (pyridin-3-ylmethyl) piperidine-3-carboxylate obtained above , 0.111 g (1.034 mmol) of phenylhydrazine was stirred at 60 ° C. for 1 hour. HPLC analysis and UPLC-MS analysis revealed the formation of a hydrazone intermediate. After cooling to room temperature, EtONa / EtOH solution (prepared by dissolving 48 mg (2.068 mmol) of Na in 3.50 mL of EtOH) was added to the reaction mixture and stirred for an additional hour at room temperature (HPLC and UPLC-MS). The reaction was measured at Then, the crude mixture was concentrated in vacuo to give a reddish residue, which was dissolved in H ₂ O2.0mL, and purified (as eluent H _{2 O,} isocratic) reversed phase chromatography by. The pure fractions in the desired product are lyophilized and the desired 2-phenyl-5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 , 3-c] pyridin-3-one 133 mg was obtained as a white solid (42% yield). 1H NMR (500 MHz, DMSO-d6): 2.41 (t, J 5.7 Hz, 1H); 2.59 (t, J 5.7 Hz, 2H); 3.03 (s, 2H); 3.62 (S, 2H); 6.75 (tt, J 7.3, 1.3 Hz, 1H); 7.12 (m, 2H); 7.36 (ddd, J 7.9, 4.7, 0.8). 9Hz, 1H); 7.74 (dt, J 7.9, 1.9Hz, 1H); 8.12 (m, 2H); 8.46 (dd, J 4.7, 1.6Hz, 1H); 8.52 (dd, J 1.9, 0.9 Hz, 1 H). 307.2.

Example 2: 3a-benzyl-5- (4-chlorobenzyl) -2-methyl-2,3a, 4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one (52) Generation of (Compound I, Scheme 1)

無水ＣＨ_２Ｃｌ_２１６．０ｍＬ中で、４−オキソピペリジン−３−カルボン酸メチル塩酸塩０．８００ｇ（４．１３４ｍｍｏｌ）と、ジイソプロピルエチルアミン１．４４ｍＬ（８．２６８ｍｍｏｌ）と、４−クロロ−ベンジルブロミド０．８５２ｇ（４．１３４ｍｍｏｌ）とを室温で撹拌した。反応をＨＰＬＣおよびＵＰＬＣ−ＭＳで測定した。室温で１６時間経過後、反応混合物に塩水を加えた。有機相を分離し、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮して、純粋な１−（４−クロロベンジル）−４−オキソピペリジン−３−カルボキン酸メチル（１．１６４ｇ、４．１３３ｍｍｏｌ、定量的収率）を得た。この生成物をさらに操作することなく次の工程で使用した。２８２．１。 (A) Methyl 1- (4-chlorobenzyl) -4-oxopiperidine-3-carboxylate (compound of formula (III), scheme 1)

In 16.0 mL of anhydrous CH ₂ Cl _2, 0.800 g (4.134 mmol) of methyl 4-oxopiperidine-3-carboxylate, 1.44 mL (8.268 mmol) of diisopropylethylamine, and 4-chloro-benzyl 0.852 g (4.134 mmol) of bromide was stirred at room temperature. The reaction was measured by HPLC and UPLC-MS. After 16 hours at room temperature, brine was added to the reaction mixture. The organic phase was separated, dried over Na ₂ SO ₄ and concentrated in vacuo to give pure methyl 1- (4-chlorobenzyl) -4-oxopiperidine-3-carboxylate (1.164 g, 4.133 mmol). , Quantitative yield). This product was used in the next step without further manipulation. 282.1.

三ッ口フラスコ中で、窒素雰囲気下、上で得た１−（４−クロロベンジル）−４−オキソピペリジン−３−カルボン酸メチル（０．８０９ｇ、２．８７１ｍｍｏｌ）の無水ＤＭＦ１．８０ｍＬ溶液に、水素化ナトリウム（０．１１５ｇ、鉱物油中６０％、２．８７１ｍｍｏｌ）を０℃で少量ずつ加えた。得られた混合物を室温で３０分間撹拌し、次いで、臭化ベンジル（０．３４１ｍＬ、２．８７１ｍｍｏｌ）の無水ＤＭＦ２．２０ｍＬ溶液を加えた。反応をＨＰＬＣおよびＵＰＬＣ−ＭＳで追った。室温で２４時間経過後、それを酢酸エチルで希釈した。有機相をＨ_２Ｏ、塩水で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮して、黄色油状物を得て、これをフラッシュクロマトグラフィー（ＳｉＯ_２、溶出液として石油エーテル：酢酸エチル ９５：５）によって精製した。純粋な画分を蒸発させ、真空下で乾燥させ、純粋な３−ベンジル−１−（４−クロロベンジル）−４−オキソピペリジン−３−カルボン酸メチルを無色油状物として得た（０．６２３ｇ、１．６７５ｍｍｏｌ、収率５８％）。３７２．２。 (B) Methyl 3-benzyl-1- (4-chlorobenzyl) -4-oxopiperidine-3-carboxylate (compound of formula (VII), scheme 1)

To a solution of methyl 1- (4-chlorobenzyl) -4-oxopiperidine-3-carboxylate (0.809 g, 2.871 mmol) obtained above in anhydrous DMF (1.80 mL) in a three-necked flask under a nitrogen atmosphere. Sodium hydride (0.115 g, 60% in mineral oil, 2.871 mmol) was added in portions at 0 ° C. The resulting mixture was stirred at room temperature for 30 minutes and then a solution of benzyl bromide (0.341 mL, 2.871 mmol) in anhydrous DMF 2.20 mL was added. The reaction was followed by HPLC and UPLC-MS. After 24 hours at room temperature, it was diluted with ethyl acetate. The organic phase was washed with H ₂ O, brine, dried over Na ₂ SO ₄ and concentrated under vacuum to give a yellow oil which was flash chromatographed (SiO ₂ , petroleum ether: acetic acid as eluent). Purified by ethyl 95: 5). The pure fractions were evaporated and dried under vacuum to give pure methyl 3-benzyl-1- (4-chlorobenzyl) -4-oxopiperidine-3-carboxylate as a colorless oil (0.623 g 1.675 mmol, 58% yield). 372.2.

(C) 3a-benzyl-5- (4-chlorobenzyl) -2-methyl-2,3a, 4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ( Compounds of formula (I), scheme 1)
In a two-necked flask under a nitrogen atmosphere in 0.9 mL of EtOH, 0.200 g of methyl 3-benzyl-1- (4-chlorobenzyl) -4-oxopiperidine-3-carboxylate obtained above (0. 538 mmol) and 0.028 mL (0.538 mmol) of methyl hydrazine were stirred at 60 ° C. for 1 hour. HPLC analysis and UPLC-MS analysis revealed the formation of a hydrazone intermediate. After cooling to room temperature, 0.062 mL (1.076 mmol) of glacial acetic acid was added. The resulting mixture was stirred at 60 ° C. and measured by HPLC and UPLC-MS. After 6 hours at 60 ° C., the crude mixture was partitioned between CH ₂ Cl ₂ and saturated aqueous NaHCO ₃ . The organic phase was separated, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil which was flash chromatographed (SiO ₂ , petroleum ether: ethyl acetate as eluent). 93: 7). The pure fractions were evaporated, dried under vacuum and the desired 3a-benzyl-5- (4-chlorobenzyl) -2-methyl-2,3a, 4,5,6,7-hexahydro-3H-pyrazolo 135 mg (0.367 mmol) of [4,3-c] pyridin-3-one was obtained as a white solid (68% yield). 1HNMR (500 MHz, DMSO-d6): 1.92 (d, J 11.0 Hz, 1H); 2.05 (td, J 11.0, 3.1 Hz, 1H); 2.75-2.81 (m , 1H); 2.89 (d, J 13.2 Hz, 1H); 2.92 (s, 3H); 2.94 (m, 1H); 3.16-3.20 (m, 1H); 3 .31 (d, J 13.2 Hz, 1 H); 3.50 (d, J 13.2 Hz, 1 H); 3.58 (d, J 13.5 Hz, 1 H); 3.68 (d, J 13. 5 Hz, 1H); 7.04 (m, 2H); 7.16-7.22 (m, 3H); 7.43 (m, 4H). 368.1.

Example 3: 5-[(4-Methylphenyl) sulfonyl] -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ( 59) Formation of (Compound Ib, Scheme I)

１−エチル−４−オキソピペリジン−３−カルボキシレート塩酸塩（市販、ＡＢＣＲ）０．２００ｇ（０．９７ｍｍｏｌ）を、トリエチルアミン０．１３５ｍＬ（０．９７ｍｍｏｌ）とともにジクロロメタン４ｍＬに溶解した。この溶液を０℃まで冷却し、パラ−トルエンスルホニルクロリド０．１８５ｇ（０．９７ｍｍｏｌ）を加えた後、トリエチルアミン０．１３５ｍＬ（０．９７ｍｍｏｌ）を加えた。反応物を０℃で２０分間撹拌し、そして室温で一晩撹拌した。次いで、反応物をさらにジクロロメタン（５０ｍＬ）で希釈し、塩水で洗浄した（２０ｍＬ×２回）。有機相をＮａ_２ＳＯ_４で乾燥させ、溶媒を蒸発させ、白色固体３００ｍｇ（収率９５％）を得た。これをさらに精製することなく次の工程で使用した。 (A) Ethyl 1-[(4-methylphenyl) sulfonyl] -4-oxopiperidine-3-carboxylate (compound of formula (III), scheme 1)

0.200 g (0.97 mmol) of 1-ethyl-4-oxopiperidine-3-carboxylate hydrochloride (commercially available, ABCR) was dissolved in 4 mL of dichloromethane together with 0.135 mL (0.97 mmol) of triethylamine. The solution was cooled to 0 ° C., 0.185 g (0.97 mmol) of para-toluenesulfonyl chloride was added, and then 0.135 mL (0.97 mmol) of triethylamine was added. The reaction was stirred at 0 ° C. for 20 minutes and stirred at room temperature overnight. The reaction was then further diluted with dichloromethane (50 mL) and washed with brine (2 × 20 mL). The organic phase was dried over Na ₂ SO ₄ and the solvent was evaporated to give 300 mg (95% yield) of a white solid. This was used in the next step without further purification.

(B) 5-[(4-Methylphenyl) sulfonyl] -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one (formula Compound of (Ib), Scheme 1)
In a three-necked flask, under nitrogen atmosphere, in EtOH 3 mL, ethyl 1-[(4-methylphenyl) sulfonyl] -4-oxopiperidine-3-carboxylate 0.300 g (0.92 mmol) and phenylhydrazine 0 0.099 g (0.92 mmol) was stirred at 50 ° C. for 1 hour. HPLC analysis and UPLC-MS analysis revealed the formation of a hydrazone intermediate. After cooling to room temperature, EtONa / EtOH solution (prepared by dissolving 42 mg of Na (1.84 mmol) in 2 mL of EtOH) was added to the reaction mixture and stirred for an additional hour at room temperature (reacted by HPLC and UPLC-MS). Measured). The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over Na ₂ SO ₄ and evaporated. The crude mixture (400 mg) was purified by flash chromatography on silica using ethyl acetate / petroleum ether (gradient up to 80/20 ethyl acetate 100%) to give the desired 5-[(4-methylphenyl) sulfonyl]- 84 mg of a white solid was obtained as 2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one (yield 25%). ¹ HNMR (500 MHz, DMSO-d6): 3.95 (s, 3H); 2.64 (t, J = 5.5 Hz, 2H); 3.17 (d, J = 5 Hz, 2H); 3.30 (Hidden by m, 2H, H2O); 7.20 (t, J = 7.25Hz, 1H); 7.40-7.45 (m, 4H); 7.65-7.7 (m, 4H); 11.36 (bs, NH); 370.

The structures of additional compounds synthesized in the present invention are listed in Table 1 below.

Table 1

Example 4: Determination of the level of reactive oxygen species in different cell cultures The activity of the compounds of the invention is tested as the activity of these compounds in inhibiting or reducing the production of reactive oxygen species (ROS) from oxygen in the cell. Can do. The activity of these compounds, nitro blue tetrazolium, Amplex Red, Chemiluminescence (Luminol), and 2 ', using different techniques such as 7'-dichlorodihydrofluorescein acetate _(H 2 DCF-DA), below The following cell cultures are tested according to the protocol described in detail.

Human microglia cell line Human microglia cell line (HMC3, human microglia clone 3) (Janabi et al., 1995, Neurosci. Lett. 195: 105), 50 U / ml penicillin G sodium, 50 μg / ml streptomycin sulfate. The cells were cultured in MEM (Eagle Minimum Essential Medium) containing 10% FBS and incubated at 37 ° C. for 24 hours. To this medium, _{O 2} ^- before detecting the production, IFN-γ (human IFN-γ, Roche.11 040 596 001 ) a final concentration was added to a 10 ng / ml at 24 hours.

Human umbilical vein endothelial cells (HUVEC)
HUVECs were hydrocortisone (1 μg / mL, CalbioChem), bovine brain extract (12 μg / mL), gentamicin ⁽ 50 μg / mL, CalbioChem), amphotericin B (50 ng / mL, CalBioChem), EGF (10 ng / mL), and 10 Incubate until the 4th passage in the basal medium for endothelium supplemented with% FCS. When the 5th passage was started, cells were cultured with a low concentration of FCS (2%) in the absence of EGF unless otherwise stated. All experiments were performed using passage 5 cells. Cells were incubated for 24 hours using OxLDL (oxidized low density lipoprotein) or its buffer as a control, after which O ₂ ⁻ production was detected.

HL-60 cells Human acute myeloid leukemia cell line HL-60 was RPMI 1640 supplemented with 10% heat-inactivated calf serum, 2 mM glutamine, 100 U / mL penicillin (Sigma), and 100 μg streptomycin (Sigma). (Invitrogen) and cultured at 37 ° C. in a humidified atmosphere of 5% CO ₂ . Differentiation of HL60 into the neutrophil phenotype was triggered by adding Me ₂ SO (final concentration of 1.25% v / v for 6 days) to the medium.

1. Nitro blue tetrazolium (NBT)
Intracellular and extracellular superoxide was measured by a colorimetric technique using a quantitative nitroblue tetrazolium (NBT) test. SOD-inhibitable conversion from NBT to formazan, a fine blue precipitate, was measured using a Fluostar Optima spectrometer (BMG labtech) in the presence of superoxide anion. After incubation with the appropriate stimulus, the cells were trypsinized (1 × Trypsin-EDTA), collected by centrifugation, washed with PBS, and the media removed. Hanks containing 0.5 mg / mL NBT with or without 800 U / mL SOD in the presence or absence of compounds of the invention, seeded with 5 × 10 ⁵ cells in 48 well plates Incubated with balanced salt solution. As a control, DPI was added at a final concentration of 10 μM. After 2.5 hours, cells were fixed and washed with methanol to remove non-reduced NBT. The reduced formazan was then dissolved in 230 μl of 2M potassium hydroxide and 280 μl of dimethyl sulfoxide. Absorbance was measured at 630 nm. For calculation, the absorbance at 630 nm was normalized for each individual well. At each time point, the average of four blank values was subtracted from each corrected value. NOX activity was expressed as% of control cell activity. The residual activity of DPI-treated cells was usually less than 10%.

2. Extracellular hydrogen peroxide was measured using Amplex Red UltraRed (Molecular Probes). Cells were trypsinized (1 × Trypsin-EDTA), collected by centrifugation and resuspended in HBSS supplemented with 1% glucose. The presence or absence of the compounds of the present invention at a density of 50,000 cells in 200 μl of test buffer (0.005 U / mL horseradish peroxidase (Roche) and 1% glucose HBSS containing 50 μM Amplex Red) Below, cells were seeded in black 96 well plates. As a control, DPI was added at a final concentration of 10 μM. The plate was placed in a fluorescent Optima Fluorescent plate reader and allowed to stand at 37 ° C. for 20 minutes. Fluorescence was measured for 15 minutes at excitation and emission wavelengths of 544 nm and 590 nm, respectively. NOX activity was expressed as% of control cell activity. The residual activity of DPI-treated cells was usually less than 10%.

以下の第３表は、上記したようなＤＭＳＯ分化ＨＬ６０細胞を用い、アンプレックスレッドによって測定したときのＮＯＸ活性のＩＣ_５０をまとめたものである。

第３表

The following Table 2 summarizes the inhibition rate of NOX activity when measured with Amplex Red using DMSO differentiated HL60 cells as described above.

Table 2

Table 3 below summarizes the IC ₅₀ of NOx activity as measured by Amplex Red using DMSO differentiated HL60 cells as described above.

Table 3

3. Chemiluminescence (Luminol)
ROS was measured using a chemiluminescent probe luminol. Cells were cultured and seeded in the same manner as Amplex Red, except that the Amplex Red agent was replaced with 10 μg / mL luminol (Sigma 09235). Luminescence was recorded continuously at 37 ° C. for 6 hours using the luminescence function of a FluoStar Optima fluorescence plate reader. At each time point, the average of four blank values was subtracted from each corrected value. NOX activity was expressed as% of control cell activity. The residual activity of DPI-treated cells was usually less than 10%.

4.2 ', 7'-dichloro-dihydro diacetate _(H 2 DCF-DA)
HUVECs were placed on coverslips and rested overnight in 0.5% BSA before stimulation with TGF-β. Cells were placed in the dark without phenol-red with 5 μM CM-H2DCFDA for 10 minutes and then treated with TGF-β (R & D Systems) in the presence or absence of compounds of the invention. Cells were then fixed and stained for nuclei with DAPI, and then visualized by immunofluorescence microscopy or examined alive using confocal microscopy. DCF fluorescence was visualized with an excitation wavelength of 488 nm and an emission wavelength of 515-540 nm. To avoid photooxidation of the indicator dye, the same parameters were used for all samples and images were collected in one rapid scan. For calculation, the absorbance at 540 nm was normalized to the absorbance at 540 nm of each individual well. At each time point, the average of four blank values was subtracted from each corrected value. NOX activity was expressed as% of control cell activity. The residual activity of DPI-treated cells was usually less than 10%.

Example 5: Blood pressure measurement in spontaneously hypertensive rats (SHR) In order to test the ability of the compounds of the invention to treat hypertension, the following assay is performed.

  An 11-week-old SHR with a systolic blood pressure exceeding 170 mmHg is used. The compounds of the invention are orally administered to rats at dosages of about 3, 10, 30, and 100 mg / kg between 10:00 and 12:00 hours. To perform a dynamic analysis of the day, mean blood pressure, systolic blood pressure, and diastolic blood pressure 2, 4, 6, 8, and 24 hours after the initial administration of the compound of the present invention, and Heart rate was monitored. For the next 2 weeks, blood pressure is monitored every 2 days in the morning at 24 hours and at the half-life of the compound.

  The 24 hour time point is monitored after the last injection. Animals are managed for an additional week without treatment to monitor compound withdrawal. Animals are treated once daily by gavage using a special needle adjusted for gavage at 5 ml / kg for 2 weeks. Acclimatize for 2 days and further acclimatize for 1 week before using the animals. The blood pressure of the awakened rat is measured by tail cuff plethysmography (Codes 6, Kent). After habituation for several days, if the SBP variation is 40 mmHg or less (ie ± 20 mmHg), animals are included in the group. Prior to the experiment, baseline measurements were performed over at least 2 days. Prior to the start of the experiment, animals are randomly extracted to form a uniform group.

Example 6: Bleomycin-induced lung injury in mice To test the ability of the compounds of the present invention to prevent or treat respiratory disorders or diseases, the following assay is performed.

  To create a lung lesion comparable to that of a respiratory disorder or disease (eg, idiopathic pulmonary fibrosis), the animal was given a sublethal dose (2.5 U / dissolved in 0.25 ml of 0.9% NaCl). kg body weight) bleomycin (BLM) is administered once intratracheally. Control animals are subjected to the same protocol, but receive the same volume of saline intratracheally instead of BLM. Intratracheal infusion is performed under anesthesia with ketamine (80 mg / kg body weight, intraperitoneal) and xylazine (20 mg / kg body weight, intraperitoneal).

  Two weeks after intratracheal administration of BLM or saline, the animals are killed by injection of a lethal dose of sodium pentobarbital, and then the abdominal aorta is phlebotomized. Bronchoalveolar lavage is performed, lungs are weighed and biochemical testing (right lung homogenized, n = 10), histological testing (left lung, n = 10) as shown below Process separately. Animals are randomly divided into 4 groups: control-saline (n = 8), and control + BLM (n = 10); compound dosage 1 + BLM (n = 10), and compound dosage 2 + BLM (N = 10). The treatment vehicle or compound is administered for 2 weeks.

  Mice are treated by daily oral administration of a compound of the invention or saline / control for 2 weeks starting on day 0. Accumulated amount of acid soluble collagen throughout the lung is analyzed by Sircol assay.

Example 7: Cancer Animal Model In order to test the ability of the compounds of the present invention to treat cancer, in particular to test the ability to reduce tumor growth and / or angiogenesis, the following assay is performed. To do.

In vivo angiogenesis assay 400 μl of Matrigel with reduced amounts of growth factors supplemented with 500 ng / ml of angiogenic factors (b-FGF or VEGF) is injected subcutaneously into 7-10 week old female C57BL6 / J. One week after transplantation, the mice are scanned using MicroCT (Skyscan). Mice are injected with tracer (400 μl iodinated liposomes) into the retro-orbital area to visualize the density of blood vessels. The scanned image is then reconstructed using the Recon program, and the gray density in the plug is measured for the entire slide of the plug. The compounds of the invention are administered orally once daily for 10 days at appropriate dosages 1 and 2. Results are expressed in gray density, which is related to blood vessel density. Also, the Matrigel plugs are frozen and stained with CD31 to visualize the blood vessels.

Tumor Growth Assay 5.10 ^Five Lewis lung cancer cells (LLC1) are injected subcutaneously into the back of mice. Mice are treated daily with 40 mg / kg of a compound of the invention orally. When the control tumor reaches approximately 1 cm in length, the mouse is sacrificed and the tumor is recovered, weighed and frozen. In the therapeutic assay, when the tumor grows to about 0.5 cm, mice are treated by injection with LLC1 cells and the size of the tumor is assessed daily. After sacrifice, tumors are frozen, tumor pieces are stained with anti-CD31 antibody, and ROS levels are analyzed.

Claims (23)

Affects cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammation and / or neurodegenerative disorders, kidney diseases, reproductive disorders, diseases affecting the eye and / or lens and / or inner ear Medical conditions, inflammatory disorders, liver diseases, pain, cancer, allergic disorders, traumatic symptoms, septic shock, hemorrhagic shock and anaphylactic shock, gastrointestinal diseases or disorders, angiogenesis, angiogenesis-dependent medical conditions, and A pyrazolopiperidine derivative of formula (I) for treating a disease or condition selected from other diseases and / or disorders associated with reducing nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase):

Wherein R ¹ is H; optionally substituted alkoxycarbonyl; optionally substituted C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl. Optionally substituted C ₂ -C ₆ alkynyl; optionally substituted alkoxy; optionally substituted alkoxy C ₁ -C ₆ alkyl; optionally substituted Aminoalkyl; optionally substituted acyl; optionally substituted aryl; optionally substituted C ₁ -C ₆ alkylaryl; optionally substituted aryl C ₁ C ₆ alkyl; optionally substituted heteroaryl; optionally substituted C ₁ -C ₆ alkylheteroaryl; if heteroaryl C ₁ may be substituted by -C ₆ alkyl; if which may C ₂ even though -C replaced by ₆ alkenyl aryl; optionally substituted aryl C ₂ even though - C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkenyl heteroaryl; optionally substituted heteroaryl C ₂ -C ₆ alkenyl; optionally substituted C ₃ -C ₈ - cycloalkyl; alkyl C ₁ -C ₆ which may be optionally substituted C ₃ -C 8 _- cycloalkyl; if good heterocycloalkyl optionally substituted optionally substituted by C ₃ -C ₈ - cycloalkyl _C 1 -C ₆ alkyl; optionally optionally substituted _C 1 -C Are those selected from alkyl heterocycloalkyl and optionally optionally substituted heterocycloalkyl C ₁ -C ₆ alkyl; R ² is, H; optionally substituted C ₁ optionally -C ₆ alkyl ; aryl which may be optionally substituted; which may C ₂ even though -C ₆ alkynyl optionally substituted; optionally substituted C ₂ -C ₆ alkenyl optionally substituted optionally hetero Optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C ₃ -C ₈ -cycloalkyl C _1- C ₆ alkyl; optionally, alkyl -C ₆ heterocycloalkyl _C 1 which may be optionally substituted Are those selected from the conversion is aryl _C 1 optionally -C ₆ alkyl and optionally optionally substituted heteroaryl _C 1 -C ₆ alkyl; ^{R 3} is, H, -S (O) - From R ⁴ , —S (O) ₂ —R ⁴ , optionally substituted C ₃ -C ₈ -cycloalkyl, optionally substituted heterocycloalkyl and —CR ⁵ R ⁶ R ⁷ R ⁴ is H; optionally substituted amino; optionally substituted C ₁ -C ₆ alkyl, eg, methyl; optionally substituted C ₂ -C ₆ alkenyl; alkoxy which may be optionally substituted; optionally substituted C ₂ -C ₆ alkynyl optionally substituted optionally alkoxy C ₁ -C ₆ alkyl, for example, when an amino alkyl optionally substituted by; aryl which may be optionally substituted; acyl which may be optionally substituted which may be optionally substituted C ₁ -C ₆ alkylaryl; optionally substituted aryl C ₁ -C ₆ alkyl, eg, optionally substituted arylmethyl; optionally substituted heteroaryl; optionally substituted Optionally substituted C ₁ -C ₆ alkyl heteroaryl; optionally substituted heteroaryl C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl aryl; optionally substituted Optionally substituted aryl C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkenyl heteroaryl; optionally substituted heteroaryl C ₂ -C ₆ alkenyl; optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted hetero Optionally substituted C ₁ -C ₆ alkyl C ₃ -C ₈ -cycloalkyl; optionally substituted C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl; are those selected from is C ₁ optionally -C ₆ alkyl heterocycloalkyl and optionally optionally substituted heterocycloalkyl C ₁ -C ₆ alkyl substituted by; R ⁵ is, H, and -CR ⁸ R ⁹ R ^{10 is} selected; R ⁶ is selected from H and —CR ¹¹ R ¹² R ¹³ R ⁷ is selected from H, —CR ¹⁴ R ¹⁵ R ¹⁶ and —C (O) —R ¹⁷ ; R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are each independently H; halogen; optionally substituted amino; optionally substituted acyl; optionally substituted Optionally C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkynyl; optionally substituted aryl; Optionally substituted C ₁ -C ₆ alkylaryl; optionally substituted aryl C ₁ -C ₆ alkyl; optionally substituted heteroaryl; Optionally substituted by multiplexer C ₁ -C ₆ alkyl heteroaryl; optionally substituted ₁ -C ₆ alkyl heteroaryl C even if; C ₂ which may be optionally substituted -C ₆ alkenyl aryl; Optionally substituted aryl C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkenyl heteroaryl; optionally substituted heteroaryl C ₂ -C ₆ alkenyl; Optionally substituted C ₃ -C ₈ -cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C ₁ -C ₆ alkyl C ₃ -C ₈ -cyclo alkyl; _C 3 which may be optionally substituted -C ₈ - cycloalkyl _C 1 -C ₆ alkyl; situ Are those selected substituted _C 1 -C ₆ alkyl heterocycloalkyl, and optionally substituted heterocycloalkyl _C 1 optionally -C ₆ alkyl ^by; -CR ^{8 R 9} R ¹⁰ , ^-CR 11 ^R 12 ^{R 13} or ^-CR 14 ^R 15 ^{R 16} are each independently, optionally aryl substituted; optionally substituted by; optionally heteroaryl optionally substituted which may C ₃ -C 8 _- is selected from cycloalkyl or optionally heterocycloalkyl optionally substituted by, optionally may form a ring which may be substituted. ]
And tautomers, geometric isomers, optically active forms, pharmaceutically acceptable salts, and pharmaceutically active derivatives thereof. A pyrazolopiperidine derivative of formula (I) for use as a medicament, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in claim 1), and tautomers, geometric isomers, optically active thereof Forms, pharmaceutically acceptable salts, and pharmaceutically active derivatives. The pyrazolopiperidine derivative according to claim 1 or 2, selected from the following group:
5-benzyl-2- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (2-chloro-4-fluorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- [3- (benzyloxy) phenyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-chloro-4-fluorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (3-chlorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- [2- (4-chlorophenoxy) ethyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2,5-dibenzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-methoxybenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (3-chlorobenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,5-dimethoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- [2- (4-chlorophenoxy) ethyl] -5- (4-methoxybenzyl) octahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,4-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,5-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (2,4-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- [4- (Benzyloxy) benzyl] -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
5- (3-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (2-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (2-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (3-methoxyphenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
5- (4-Chlorobenzyl) -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3- on;
5- (4-chlorobenzyl) -2- (3-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (2-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (3-methoxyphenyl) -5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-methoxybenzyl) -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Methoxybenzyl) -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3- on;
5- (4-chlorobenzyl) -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Methoxybenzyl) -2- (2-morpholin-4-ylethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
2- (1,3-Benzodioxol-5-yl) -5- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] Pyridin-3-one;
2- (1,3-Benzodioxol-5-yl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] Pyridin-3-one;
5- (2,4-dichlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (4-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-phenyl-5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-methoxybenzyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (3-methoxybenzyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-[(2-benzyl-3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzonitrile;
2- (2-hydroxyethyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (1,3-benzodioxol-5-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridine -5-yl] methyl} benzonitrile;
3- [5- (4-chlorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
5- (4-chlorobenzyl) -2- (2-hydroxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Chlorobenzyl) -2- (2-morpholin-4-ylethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
3a-benzyl-5- (4-chlorobenzyl) -2-methyl-2,3a, 4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (2-phenoxyethyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-Methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c ] Pyridin-5-yl] methyl} benzonitrile;
N- {4-[(3-oxo-2-phenyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] phenyl} acetamide ;
N-methyl-4-[(3-oxo-2-phenyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzamide;
4- [5- (4-chlorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
5- (methylsulfonyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-[(4-methylphenyl) sulfonyl] -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-hydroxyethyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
4-{[2- (4-Chlorophenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzonitrile ;
2- (1,3-benzodioxol-5-yl) -5- (3-chloro-4-fluorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 3-c] pyridin-3-one;
5- (3-Chloro-4-fluorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [ 4,3-c] pyridin-3-one;
4-{[2- (3-methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- [4- (methylsulfonyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 , 3-c] pyridin-3-one;
5- (4-Chlorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3- c] pyridin-3-one;
2-Benzyl-5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
3-{[2- (2-Methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c ] Pyridin-5-yl] methyl} benzonitrile;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
3-[(2-benzyl-3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzonitrile;
4-{[2- (4-Methoxyphenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
3-Fluoro-4-{[2- (2-methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4 , 3-c] pyridin-5-yl] methyl} benzonitrile;
2- (1,3-Benzodioxol-5-yl) -5- [4- (methylsulfonyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
2- (1,3-benzodioxol-5-yl) -5- [3- (trifluoromethyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 3-c] pyridin-3-one;
2- (3-methoxybenzyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-methoxybenzyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
2- (4-chlorophenyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
3- [3-oxo-5- (pyridin-3-ylmethyl) -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
4-{[3-oxo-2- (2-piperidin-1-ylethyl) -1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] Methyl} benzonitrile;
N- {3- [3-oxo-5- (pyridin-3-ylmethyl) -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] Phenyl} acetamide;
2- (2-fluorophenyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-Fluorophenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
5-[(6-Chloropyridin-3-yl) methyl] -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine -3-one;
N- {3- [5- (3-Chloro-4-fluorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl] phenyl} acetamide;
4-{[2- (4-Methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
5- (4-Chlorobenzyl) -2-methyl-3a- (pyridin-3-ylmethyl) -2,3a, 4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3 -ON;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- [3- (trifluoromethyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [ 4,3-c] pyridin-3-one;
5- (3-Chloro-4-fluorobenzyl) -2- (4-chlorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
3- [5- (3-Chloro-4-fluorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] Benzonitrile;
3- {3-oxo-5- [3- (trifluoromethyl) benzyl] -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl} Benzonitrile;
3- {5-[(6-chloropyridin-3-yl) methyl] -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl} benzonitrile;
2-Benzyl-5- (3-chloro-4-fluorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (4-Chlorophenyl) -5-[(6-chloropyridin-3-yl) methyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine 3-on;
5-[(6-Chloropyridin-3-yl) methyl] -2- (2-fluorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine -3-one;
5-[(6-Chloropyridin-3-yl) methyl] -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
2-Benzyl-5-[(6-chloropyridin-3-yl) methyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4- {5-[(6-chloropyridin-3-yl) methyl] -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl} benzonitrile;
2-Benzyl-5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
5- (2-Chlorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3- c] pyridin-3-one;
2-benzyl-5- (methylsulfonyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one; and 2- (imidazo [1,2 -A] pyridin-2-ylmethyl) -5-[(4-methylphenyl) sulfonyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3- on. Pyrazolopiperidine derivatives of formula (I) wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in any one of claims 1 to 3; R ³ is —S (O) —R ⁴ , —S (O) _{It is selected from 2-} R ⁴ , optionally substituted C ₃ -C ₈ -cycloalkyl, optionally substituted heterocycloalkyl, and —CR ⁵ R ⁶ R ⁷ . ), And tautomers, geometric isomers, optically active forms, pharmaceutically acceptable salts, and pharmaceutically active derivatives thereof, wherein the compound is selected from the group consisting of: Compounds not to be:
5-methyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-ethyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-phenyl-5-propyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-butyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (3-methylbutyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-Benzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one. R ¹ is selected from optionally substituted aryl and optionally substituted heteroaryl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in any of the preceding claims. The derivative | guide_body as described in any one of Claims 1-4. R ¹ is optionally substituted C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl; optionally substituted C ₂ -C ₆ alkynyl R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ 5. A derivative according to any one of claims 1 to 4, wherein and R ¹⁷ are as defined in any one of the preceding claims. R ¹ is selected from optionally substituted aryl C ₁ -C ₆ alkyl, and optionally substituted heteroaryl C ₁ -C ₆ alkyl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are any of the preceding claims The derivative according to any one of claims 1 to 4, which is as defined in claim 1. R ¹ is an optionally substituted heterocycloalkyl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² 5. The derivative according to claim 1, wherein R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in any one of the preceding claims. . R ¹ is optionally substituted heterocycloalkyl C ₁ -C ₆ alkyl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in any one of the preceding claims. The derivative according to one item. R ¹ is optionally substituted alkoxy C ₁ -C ₆ alkyl; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^11. R 1, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are as defined in any one of the preceding claims. Derivatives described in 1. R ² is H; R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R 11. A derivative according to any one of claims 1 to 10, wherein ¹⁶ and R ¹⁷ are as defined in any one of the preceding claims. R ² is selected from optionally substituted aryl C ₁ -C ₆ alkyl, and optionally substituted heteroaryl C ₁ -C ₆ alkyl; R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are any of the preceding claims The derivative according to any one of claims 1 to 10, which is as defined in claim 1. R ³ is —CR ⁵ R ⁶ R ⁷ ; R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ^15, R ¹⁶ and R ¹⁷ are those as defined in any one of the preceding claims, derivative according to any one of claims 1 to 12. R ³ is _{^{S (O) 2 -R 4;}} R 1, R 2 and ^{R 4,} are those as defined in any one of the preceding claims, any claims 1-12 The derivative according to claim 1. R ³ is S (O) ₂ -R ⁴ , R ⁴ is optionally substituted C ₁ -C ₆ alkyl; optionally substituted C ₂ -C ₆ alkenyl, and 15. C ₂ -C ₆ alkynyl optionally substituted by: R ¹ and R ² are as defined in any one of the preceding claims. Derivatives described in 1. R ³ is S (O) ₂ -R ⁴ and R ⁴ is selected from optionally substituted aryl, and optionally substituted heteroaryl; R ¹ and R ² is of as defined in any one of the preceding claims, derivative according to claim 14. The derivative according to any one of claims 4 to 16, which is selected from the following group:
5-benzyl-2- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (2-chloro-4-fluorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- [3- (benzyloxy) phenyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (3-chlorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- [2- (4-chlorophenoxy) ethyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2,5-dibenzyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-methoxybenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (3-chlorobenzyl) -2-methyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,5-dimethoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- [2- (4-chlorophenoxy) ethyl] -5- (4-methoxybenzyl) octahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,4-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (3,5-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-Benzyl-5- (2,4-dichlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- [4- (Benzyloxy) benzyl] -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
5- (3-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-benzyl-2- (2-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (2-chlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (3-methoxyphenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile 5- (4-Chlorobenzyl) -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3 -ON;
5- (4-chlorobenzyl) -2- (3-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (2-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (3-methoxyphenyl) -5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-methoxybenzyl) -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Methoxybenzyl) -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3- on;
5- (4-chlorobenzyl) -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Methoxybenzyl) -2- (2-morpholin-4-ylethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
2- (1,3-Benzodioxol-5-yl) -5- (4-chlorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] Pyridin-3-one;
2- (1,3-Benzodioxol-5-yl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] Pyridin-3-one;
5- (2,4-dichlorobenzyl) -2- (3-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-chlorobenzyl) -2- (4-methoxyphenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2-phenyl-5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-methoxybenzyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (3-methoxybenzyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-[(2-benzyl-3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzonitrile;
2- (2-hydroxyethyl) -5- (4-methoxybenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (1,3-benzodioxol-5-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridine -5-yl] methyl} benzonitrile;
3- [5- (4-chlorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
5- (4-chlorobenzyl) -2- (2-hydroxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (4-Chlorobenzyl) -2- (2-morpholin-4-ylethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
3a-benzyl-5- (4-chlorobenzyl) -2-methyl-2,3a, 4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5- (2-phenoxyethyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-Methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c ] Pyridin-5-yl] methyl} benzonitrile;
N- {4-[(3-oxo-2-phenyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] phenyl} acetamide ;
N-methyl-4-[(3-oxo-2-phenyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzamide;
4- [5- (4-chlorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
5- (methylsulfonyl) -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
5-[(4-methylphenyl) sulfonyl] -2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-hydroxyethyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
4-{[2- (4-Chlorophenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzonitrile ;
2- (1,3-benzodioxol-5-yl) -5- (3-chloro-4-fluorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 3-c] pyridin-3-one;
5- (3-Chloro-4-fluorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [ 4,3-c] pyridin-3-one;
4-{[2- (3-methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- [4- (methylsulfonyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 , 3-c] pyridin-3-one;
5- (4-Chlorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3- c] pyridin-3-one;
2-Benzyl-5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
3-{[2- (2-Methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c ] Pyridin-5-yl] methyl} benzonitrile;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
3-[(2-benzyl-3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl) methyl] benzonitrile;
4-{[2- (4-Methoxyphenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
3-Fluoro-4-{[2- (2-methyl-1,3-benzothiazol-6-yl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4 , 3-c] pyridin-5-yl] methyl} benzonitrile;
2- (1,3-Benzodioxol-5-yl) -5- [4- (methylsulfonyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
2- (1,3-benzodioxol-5-yl) -5- [3- (trifluoromethyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4 3-c] pyridin-3-one;
2- (3-methoxybenzyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-methoxybenzyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
2- (4-chlorophenyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
3- [3-oxo-5- (pyridin-3-ylmethyl) -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] benzonitrile;
4-{[3-oxo-2- (2-piperidin-1-ylethyl) -1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] Methyl} benzonitrile;
N- {3- [3-oxo-5- (pyridin-3-ylmethyl) -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] Phenyl} acetamide;
2- (2-fluorophenyl) -5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4-{[2- (2-Fluorophenyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
5-[(6-Chloropyridin-3-yl) methyl] -2- (2-methoxyethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine -3-one;
N- {3- [5- (3-Chloro-4-fluorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl] phenyl} acetamide;
4-{[2- (4-Methoxybenzyl) -3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo [4,3-c] pyridin-5-yl] methyl} benzo Nitrile;
5- (4-Chlorobenzyl) -2-methyl-3a- (pyridin-3-ylmethyl) -2,3a, 4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3 -ON;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- [3- (trifluoromethyl) benzyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [ 4,3-c] pyridin-3-one;
5- (3-Chloro-4-fluorobenzyl) -2- (4-chlorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one ;
3- [5- (3-Chloro-4-fluorobenzyl) -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl] Benzonitrile;
3- {3-oxo-5- [3- (trifluoromethyl) benzyl] -1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridin-2-yl} Benzonitrile;
3- {5-[(6-chloropyridin-3-yl) methyl] -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl} benzonitrile;
2-Benzyl-5- (3-chloro-4-fluorobenzyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (4-Chlorophenyl) -5-[(6-chloropyridin-3-yl) methyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine 3-on;
5-[(6-Chloropyridin-3-yl) methyl] -2- (2-fluorophenyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine -3-one;
5-[(6-Chloropyridin-3-yl) methyl] -2- (1-methylpiperidin-4-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
2-Benzyl-5-[(6-chloropyridin-3-yl) methyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
4- {5-[(6-chloropyridin-3-yl) methyl] -3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c] pyridine-2 -Yl} benzonitrile;
2-Benzyl-5- (pyridin-3-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one;
2- (2-Methyl-1,3-benzothiazol-6-yl) -5- (pyridin-2-ylmethyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3 -C] pyridin-3-one;
5- (2-Chlorobenzyl) -2- (2-methyl-1,3-benzothiazol-6-yl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3- c] pyridin-3-one;
2-benzyl-5- (methylsulfonyl) -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridin-3-one; and 2- (imidazo [1,2 -A] pyridin-2-ylmethyl) -5-[(4-methylphenyl) sulfonyl] -1,2,4,5,6,7-hexahydro-3H-pyrazolo [4,3-c] pyridine-3- on.   A pharmaceutical composition comprising at least one derivative according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier, diluent or excipient thereof.   Affects cardiovascular disorders, respiratory disorders, metabolic disorders, skin disorders, bone disorders, neuroinflammation and / or neurodegenerative disorders, kidney diseases, reproductive disorders, diseases affecting the eye and / or lens and / or inner ear Medical conditions, inflammatory disorders, liver diseases, pain, cancer, allergic disorders, traumatic symptoms, septic shock, hemorrhagic shock and anaphylactic shock, gastrointestinal diseases or disorders, angiogenesis, angiogenesis-dependent medical conditions, and A method of treating a patient suffering from a disease or condition selected from other diseases and / or disorders associated with reducing nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), the method comprising: Administering a compound according to any one of claims 1 to 17 to a patient   A method of inhibiting angiogenesis in a patient in need thereof, the method comprising inhibiting the angiogenesis of a compound according to any one of claims 1 to 17 to a patient in need thereof. Administering a dosage.   20. The method of claim 19, wherein the disease or condition is cancer.   21. The method according to claim 19 or 20, characterized in that the compound according to any one of claims 1 to 17 is administered in combination with an adjuvant useful for the treatment of cancer. 21. A method according to claim 19 or 20, characterized in that the compound according to any one of claims 1 to 17 is administered in combination with radiation therapy.